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Yang L, Xiao JJ, Zhang L, Lu Q, Hu BB, Liu Y, Pu JX, Hu JW, Yu H, Wu X, Zhang BF. Methionine sulfoxide reductase A deficiency aggravated ferroptosis in LPS-induced acute kidney injury by inhibiting the AMPK/NRF2 axis and activating the CaMKII/HIF-1α pathway. Free Radic Biol Med 2025; 234:248-263. [PMID: 40288699 DOI: 10.1016/j.freeradbiomed.2025.04.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/13/2025] [Accepted: 04/25/2025] [Indexed: 04/29/2025]
Abstract
Methionine sulfoxide reductase A (MsrA) is an important antioxidant enzyme that is present in various tissues and play a crucial role in many pathological processes. However, the role of MsrA in acute kidney injury (AKI) requires further exploration. Here, we aimed to explore whether MsrA is involved in sepsis-associated AKI and the underlying mechanisms. In the present study, AKI was induced by lipopolysaccharide (LPS) in WT mice and MsrA knockout mice. The role of MsrA in LPS-induced injury in the human renal proximal tubule epithelial cell line HK-2 was also examined by MsrA knockdown. MsrA deficiency exacerbated LPS-induced kidney damage in vivo. In addition, MsrA deficiency and silencing intensified iron overload, lipid peroxidation and ferroptosis in LPS-stimulated renal tubular cells. The mechanistic study revealed that MsrA knockout or knockdown led to the oxidation of calcium/calmodulin-dependent protein kinase II (CaMKII) at methionine 281/282, resulting in sustained activation of CaMKII, which upregulated iron metabolism-related proteins such as transferrin receptor 1 (TFR1) by promoting phosphorylation and nuclear translocation of hypoxia-inducible factor-1α (HIF-1α) and induced abnormal iron metabolism. Meanwhile, CaMKII activation downregulated the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) by inhibiting the activity of AMP-activated protein kinase (AMPK) and phosphorylation of nuclear factor erythroid 2-related factor 2 (NRF2), resulting in lipid peroxidation. Consequently, LPS-induced ferroptosis was exacerbated. Our study is the first to reveal that MsrA deficiency intensifies LPS-induced ferroptosis through CaMKII activation in renal tubular cells. There are two major mechanisms: one is the promotion of lipid peroxidation by inhibiting the AMPK/NRF2 axis, and the other is abnormal iron metabolism by activating the HIF-1α/TFR1 pathway. MsrA may be a potential therapeutic target for organ and cell damage induced by ferroptosis.
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Affiliation(s)
- LiJiao Yang
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jing-Jie Xiao
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China; Department of Cardiology, Zhongnan Hospital of Wuhan University, Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, 430071, China
| | - Lian Zhang
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - QianYu Lu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bin-Bin Hu
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Yu Liu
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Jun-Xing Pu
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Jun-Wei Hu
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Hong Yu
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.
| | - XiaoYan Wu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China.
| | - Bai-Fang Zhang
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.
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Hu Q, Zhang J, Luo X, Hu P, Li J, Li F, Wang Z, Zhang S, Jiao Z, Liu Y, Duanmu J, Jin L, Xie P, Zhu W, Zheng W, Shang H, Hu X, Chen Z, Xiao RP, Zhang Y. Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury. Circulation 2025. [PMID: 40396239 DOI: 10.1161/circulationaha.124.070936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 04/09/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Myocardial ischemia/reperfusion (I/R) injury is a substantial challenge to the management of ischemic heart disease, the leading cause of mortality worldwide. Arachidonic acid (AA) is a prominent polyunsaturated fatty acid in the human body and plays an important role in various physiological and pathological conditions. AA metabolic enzymes determine AA levels; however, currently there is no comprehensive analysis of AA enzymes in cardiac I/R injury. METHODS The profiling of AA metabolic enzymes was analyzed with the RNA sequencing transcriptome data from the mouse heart tissues with I/R injury. Cultured neonatal and adult rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse I/R models were used to confirm the role of L-PGDS (lipocalin-type prostaglandin D2 synthase)/15d-PGJ2 in I/R injury. A biotin-tagged 15d-PGJ2 analog combined with liquid chromatography-tandem mass spectrometry was used to identify the downstream signaling of L-PGDS/15d-PGJ2. RESULTS Based on the transcriptome data and experimental validations, L-PGDS, together with its downstream metabolite 15d-PGJ2, was downregulated in cardiac tissue with I/R injury. Functionally, L-PGDS overexpression mitigates myocardial I/R injury, whereas knockdown exacerbates the damage. Supplementation of 15d-PGJ2 alleviated I/R injury. Mechanistically, 15d-PGJ2 covalently bound to the Ca2+/CaMKII (calmodulin protein kinase II) and induced lipoxidation of its cysteine 495 (CaMKII-δ9) to dampen the formation of CaMKII oligomers and alleviate its overactivation, consequently ameliorating cardiomyocyte death and cardiac injury. CONCLUSIONS Our study uncovered L-PGDS/15d-PGJ2/CaMKII signaling as a new mechanism underlying I/R-induced cardiomyocyte death. This provides new mechanistic insights and therapeutic targets for myocardial I/R injury and subsequent heart failure. We also showed that lipoxidation is a new post-translational modification type for CaMKII, deepening our understanding of the regulation of its activity.
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Affiliation(s)
- Qingmei Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
| | - Junxia Zhang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, China. (J.Z.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (J.Z., Y.Z.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing, China (J.Z.)
| | - Xile Luo
- Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, China. (X.L., X.D., Y.Z.)
| | - Peiyu Hu
- Institute of Energy, Peking University, China. (P.H.)
| | - Jiayi Li
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
| | - Fan Li
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
| | - Zeyuan Wang
- Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. (Z.W., S.Z.)
| | - Shuyang Zhang
- Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. (Z.W., S.Z.)
| | - Zishan Jiao
- Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. (Z.J.)
| | - Yitong Liu
- Peking-Tsinghua Center for Life Sciences, Peking University, China. (Y.L., W. Zhu, Z.C., R.-P.X.)
| | | | - Li Jin
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
| | - Peng Xie
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
| | - Wenneng Zhu
- Peking-Tsinghua Center for Life Sciences, Peking University, China. (Y.L., W. Zhu, Z.C., R.-P.X.)
- Department of Chemical Biology, College of Chemistry, Peking University, China. (W. Zhu)
| | - Wen Zheng
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
| | - Haibao Shang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
| | - Xinli Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
| | - Zhixing Chen
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
- Peking-Tsinghua Center for Life Sciences, Peking University, China. (Y.L., W. Zhu, Z.C., R.-P.X.)
| | - Rui-Ping Xiao
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, China. (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.)
- Peking-Tsinghua Center for Life Sciences, Peking University, China. (Y.L., W. Zhu, Z.C., R.-P.X.)
- Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, China. (R.-P.X.)
- PKU-Nanjing Joint Institute of Translational Medicine, China (R.-P.X.)
| | - Yan Zhang
- Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, China. (X.L., X.D., Y.Z.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (J.Z., Y.Z.)
- NHC Key Laboratory of Cell Transplantation, First Affiliated Hospital of Harbin Medical University, China (Y.Z.)
- Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (Y.Z.)
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Zhang K, Wang S, Li X, Cui H, Lai Y. Mechanism of Ion Channel Impairment in the Occurrence of Arrhythmia in Patients with Hypertrophic Cardiomyopathy. Cardiol Rev 2025; 33:260-264. [PMID: 37812010 PMCID: PMC11969372 DOI: 10.1097/crd.0000000000000612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Sudden cardiac death is the most unpredictable and devastating consequence of hypertrophic cardiomyopathy, most often caused by persistent ventricular tachycardia or ventricular fibrillation. Although myocardial hypertrophy, fibrosis, and microvascular disorders are the main mechanisms of persistent reentrant ventricular arrhythmias in patients with advanced hypertrophic cardiomyopathy, the cardiomyocyte mechanism based on ion channel abnormalities may play an important role in the early stages of the disease.
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Affiliation(s)
- Ke Zhang
- From the Department of Cardiovascular Surgery
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Shengwei Wang
- From the Department of Cardiovascular Surgery
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Xiaoyan Li
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Hao Cui
- From the Department of Cardiovascular Surgery
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Yongqiang Lai
- From the Department of Cardiovascular Surgery
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
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Lei M, Wu L, Terrar DA, Huang CLH. The modernized classification of cardiac antiarrhythmic drugs: Its application to clinical practice. Heart Rhythm 2025:S1547-5271(25)02300-8. [PMID: 40187508 DOI: 10.1016/j.hrthm.2025.03.1997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/19/2025] [Accepted: 03/29/2025] [Indexed: 04/07/2025]
Abstract
Cardiac arrhythmias pose a major public health problem, and pharmacologic intervention remains key to their therapy. The 1970 landmark Vaughan Williams (VW) classification utilizing known actions of then available antiarrhythmic drugs (AADs) became and remains central to management, but it requires revision in response to extensive subsequent advances. Our modernized AAD classification reflected and sought to facilitate such fundamental physiological and clinical development. Here we respond to requests for an adaptation of our scheme specifically focused on clinical practice. (1) This adaptation improves the accessibility of our original scheme to clinical practice, focusing on key AADs in clinical use rather than investigational new drugs (INDs) while conserving and encompassing the classic VW scheme. (2) We preserve a rational conceptual framework based on current understanding of the relevant electrophysiological events, their underlying cellular or molecular cardiomyocyte targets, and the functional mechanisms they mediate. (3) The adopted subclasses within each AAD class parallel clinical practice by including only subclasses containing established AADs, or approved potential off-label drugs, as opposed to those only including INDs. (4) The simplified scheme remains flexible, permitting drugs to be placed in multiple classes where required, and the addition of classes and subclasses in light of future investigations and clinical approvals. Thus, we derive from our comprehensive modernized AAD classification a more focused and simpler scheme for clinical use. This both modernizes yet preserves the classic VW classification and remains flexible, thus accommodating future developments.
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Affiliation(s)
- Ming Lei
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
| | - Lin Wu
- Department of Cardiology, Peking University First Hospital, Beijing, China.
| | - Derek A Terrar
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Christopher L-H Huang
- Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
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Zhu H, Hu B, Zhang H, Li H, Zhou J, Jing Z. Serum Ionized Calcium as a Prognostic Biomarker in Type B Aortic Dissection After Endovascular Treatment. J Endovasc Ther 2025; 32:121-129. [PMID: 37158680 DOI: 10.1177/15266028231168348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
OBJECTIVE Lower serum ionized calcium (iCa2+) was reported to be associated with a higher risk of adverse events in patients with cardiovascular diseases. This study aimed to investigate the associations between preoperative serum iCa2+ and outcomes of type B aortic dissection (TBAD) patients receiving thoracic endovascular aortic repair (TEVAR). METHODS Between January 2016 and December 2019, 491 TBAD patients received TEVAR in a single center. Patients with acute or subacute TBAD were included. Serum iCa2+ (pH 7.4) was obtained from the arterial blood gas analysis before TEVAR. The study population was grouped into the hi-Ca group (1.11 mmol/L ≤ iCa2+ < 1.35 mmol/L) and lo-Ca group (iCa2+ < 1.11 mmol/L). The primary outcomes were all-cause mortality. The secondary outcomes were any major adverse clinical events (MACEs), which included all-cause mortality and aortic-related severe complications. To eliminate bias, 1:1 propensity score matching (PSM) was conducted. RESULTS Overall, 396 TBAD patients were included in this study. In the total population, there were 119 (30.1%) patients in the lo-Ca group. After PSM, 77 matched pairs were obtained for further analysis. In the matched population, the 30-day mortality and 30-day MACEs between the two groups presented significant differences (p=0.023 and 0.029, respectively). At 5 years, cumulative incidences of mortality (log-rank p<0.001) and MACEs (log-rank p=0.016) were significantly higher in the lo-Ca group than that of the hi-Ca group. Multivariate cox regression analysis indicated that lower preoperative iCa2+ (hazard ratio for per 0.1 mmol/L decrease, 2.191; 95% confidence interval, 1.487-3.228, p<0.001) was an independent risk factor for 5-year mortality after PSM. CONCLUSIONS Lower preoperative serum iCa2+ might have an association with 5-year mortality in TBAD patients after TEVAR. Serum iCa2+ monitoring in this population may facilitate the identification of critical conditions. CLINICAL IMPACT Our present study found that the cutoff value of preoperative serum iCa2+ 1.11 mmol/L, which is slightly lower than the lower limit of the normal range of 1.15-1.35 mmol/L, worked relatively well for discerning the high-risk and low-risk TBAD patients at 5 years. Serum iCa2+ monitoring in TBAD patients receiving TEVAR may facilitate the identification of critical conditions.
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Affiliation(s)
- Hongqiao Zhu
- Department of Vascular Surgery, The First Affiliated Hospital of the Navy Medical University (Changhai Hospital), Shanghai, China
| | - Bei Hu
- Department of Vascular Surgery, The First Affiliated Hospital of the Navy Medical University (Changhai Hospital), Shanghai, China
| | - Heng Zhang
- Department of Vascular Surgery, The First Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Haiyan Li
- Department of Vascular Surgery, The First Affiliated Hospital of the Navy Medical University (Changhai Hospital), Shanghai, China
| | - Jian Zhou
- Department of Vascular Surgery, The First Affiliated Hospital of the Navy Medical University (Changhai Hospital), Shanghai, China
- Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai, China
| | - Zaiping Jing
- Department of Vascular Surgery, The First Affiliated Hospital of the Navy Medical University (Changhai Hospital), Shanghai, China
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Al Ali HS, Rodrigo GC, Lambert DG. Signalling pathways involved in urotensin II induced ventricular myocyte hypertrophy. PLoS One 2025; 20:e0313119. [PMID: 39820183 PMCID: PMC11737703 DOI: 10.1371/journal.pone.0313119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 10/20/2024] [Indexed: 01/19/2025] Open
Abstract
Sustained pathologic myocardial hypertrophy can result in heart failure(HF); a significant health issue affecting a large section of the population worldwide. In HF there is a marked elevation in circulating levels of the peptide urotensin II(UII) but it is unclear whether this is a result of hypertrophy or whether the high levels contribute to the development of hypertrophy. The aim of this study is to investigate a role of UII and its receptor UT in the development of cardiac hypertrophy and the signalling molecules involved. Ventricular myocytes isolated from adult rat hearts were treated with 200nM UII for 48hours and hypertrophy was quantified from measurements of length/width (L/W) ratio. UII resulted in a change in L/W ratio from 4.53±0.10 to 3.99±0.06; (p<0.0001) after 48hours. The response is reversed by the UT-antagonist SB657510 (1μM). UT receptor activation by UII resulted in the activation of ERK1/2, p38 and CaMKII signalling pathways measured by Western blotting; these are involved in the induction of hypertrophy. JNK was not involved. Moreover, ERK1/2, P38 and CaMKII inhibitors completely blocked UII-induced hypertrophy. Sarcoplasmic reticulum (SR) Ca2+-leak was investigated in isolated myocytes. There was no significant increase in SR Ca2+-leak. Our results suggest that activation of MAPK and CaMKII signalling pathways are involved in the hypertrophic response to UII. Collectively our data suggest that increased circulating UII may contribute to the development of left ventricular hypertrophy and pharmacological inhibition of the UII/UT receptor system may prove beneficial in reducing adverse remodeling and alleviating contractile dysfunction in heart disease.
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Affiliation(s)
- Hadeel S. Al Ali
- Department of Cardiovascular Sciences, Clinical Sciences Wing, Glenfield Hospital, University of Leicester, Leicester, United Kingdom
- Department of Physiology, Al-Zahraa College of Medicine, University of Basrah, Basrah, Iraq
| | - Glenn C. Rodrigo
- Department of Cardiovascular Sciences, Clinical Sciences Wing, Glenfield Hospital, University of Leicester, Leicester, United Kingdom
| | - David G. Lambert
- Department of Cardiovascular Sciences, Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester, United Kingdom
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Martinez-Canton M, Gallego-Selles A, Galvan-Alvarez V, Garcia-Gonzalez E, Garcia-Perez G, Santana A, Martin-Rincon M, Calbet JAL. CaMKII protein expression and phosphorylation in human skeletal muscle by immunoblotting: Isoform specificity. Free Radic Biol Med 2024; 224:182-189. [PMID: 39187050 DOI: 10.1016/j.freeradbiomed.2024.08.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 08/17/2024] [Accepted: 08/23/2024] [Indexed: 08/28/2024]
Abstract
Calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMKII) is activated during exercise by reactive oxygen species (ROS) and Ca2+ transients initiating muscle contraction. CaMKII modulates antioxidant, inflammatory, metabolic and autophagy signalling pathways. CaMKII is coded by four homologous genes (α, β, γ, and δ). In rat skeletal muscle, δD, δA, γD, γB and βM have been described while different characterisations of human skeletal muscle CaMKII isoforms have been documented. Precisely discerning between the various isoforms is pivotal for understanding their distinctive functions and regulatory mechanisms in response to exercise and other stimuli. This study aimed to optimize the detection of the different CaMKII isoforms by western blotting using eight different CaMKII commercial antibodies in human skeletal muscle. Exercise-induced posttranslational modifications, i.e. phosphorylation and oxidations, allowed the identification of specific bands by multitargeting them with different antibodies after stripping and reprobing. The methodology proposed has confirmed the molecular weight of βM CaMKII and allows distinguishing between γ/δ and δD CaMKII isoforms. The corresponding molecular weight for the CaMKII isoforms resolved were: δD, at 54.2 ± 2.1 kDa; γ/δ, at 59.0 ± 1.2 kDa and 61.6 ± 1.3 kDa; and βM isoform, at 76.0 ± 1.8 kDa. Some tested antibodies showed high specificity for the δD, the most responsive isoform to ROS and intracellular Ca2+ transients in human skeletal muscle, while others, despite the commercial claims, failed to show such specificity.
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Affiliation(s)
- Miriam Martinez-Canton
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira S/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain
| | - Angel Gallego-Selles
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira S/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain
| | - Victor Galvan-Alvarez
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira S/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain
| | - Eduardo Garcia-Gonzalez
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira S/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain
| | - Giovanni Garcia-Perez
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira S/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain
| | - Alfredo Santana
- Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain; Complejo Hospitalario Universitario Insular-Materno Infantil de Las Palmas de Gran Canaria, Clinical Genetics Unit, 35016, Las Palmas de Gran Canaria, Spain
| | - Marcos Martin-Rincon
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira S/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain.
| | - Jose A L Calbet
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira S/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain; School of Kinesiology, Faculty of Education, The University of British Columbia, Vancouver, BC, Canada; Department of Physical Performance, The Norwegian School of Sport Sciences, Postboks, 4014 Ulleval Stadion, 0806, Oslo, Norway.
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Yong J, Song J. CaMKII activity and metabolic imbalance-related neurological diseases: Focus on vascular dysfunction, synaptic plasticity, amyloid beta accumulation, and lipid metabolism. Biomed Pharmacother 2024; 175:116688. [PMID: 38692060 DOI: 10.1016/j.biopha.2024.116688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/03/2024] Open
Abstract
Metabolic syndrome (MetS) is characterized by insulin resistance, hyperglycemia, excessive fat accumulation and dyslipidemia, and is known to be accompanied by neuropathological symptoms such as memory loss, anxiety, and depression. As the number of MetS patients is rapidly increasing globally, studies on the mechanisms of metabolic imbalance-related neuropathology are emerging as an important issue. Ca2+/calmodulin-dependent kinase II (CaMKII) is the main Ca2+ sensor and contributes to diverse intracellular signaling in peripheral organs and the central nervous system (CNS). CaMKII exerts diverse functions in cells, related to mechanisms such as RNA splicing, reactive oxygen species (ROS) generation, cytoskeleton, and protein-protein interactions. In the CNS, CaMKII regulates vascular function, neuronal circuits, neurotransmission, synaptic plasticity, amyloid beta toxicity, lipid metabolism, and mitochondrial function. Here, we review recent evidence for the role of CaMKII in neuropathologic issues associated with metabolic disorders.
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Affiliation(s)
- Jeongsik Yong
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do, Republic of Korea.
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Chacar S, Abdi A, Almansoori K, Alshamsi J, Al Hageh C, Zalloua P, Khraibi AA, Holt SG, Nader M. Role of CaMKII in diabetes induced vascular injury and its interaction with anti-diabetes therapy. Rev Endocr Metab Disord 2024; 25:369-382. [PMID: 38064002 PMCID: PMC10943158 DOI: 10.1007/s11154-023-09855-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/16/2023] [Indexed: 03/16/2024]
Abstract
Diabetes mellitus is a metabolic disorder denoted by chronic hyperglycemia that drives maladaptive structural changes and functional damage to the vasculature. Attenuation of this pathological remodeling of blood vessels remains an unmet target owing to paucity of information on the metabolic signatures of this process. Ca2+/calmodulin-dependent kinase II (CaMKII) is expressed in the vasculature and is implicated in the control of blood vessels homeostasis. Recently, CaMKII has attracted a special attention in view of its chronic upregulated activity in diabetic tissues, yet its role in the diabetic vasculature remains under investigation.This review highlights the physiological and pathological actions of CaMKII in the diabetic vasculature, with focus on the control of the dialogue between endothelial (EC) and vascular smooth muscle cells (VSMC). Activation of CaMKII enhances EC and VSMC proliferation and migration, and increases the production of extracellular matrix which leads to maladaptive remodeling of vessels. This is manifested by activation of genes/proteins implicated in the control of the cell cycle, cytoskeleton organization, proliferation, migration, and inflammation. Endothelial dysfunction is paralleled by impaired nitric oxide signaling, which is also influenced by CaMKII signaling (activation/oxidation). The efficiency of CaMKII inhibitors is currently being tested in animal models, with a focus on the genetic pathways involved in the regulation of CaMKII expression (microRNAs and single nucleotide polymorphisms). Interestingly, studies highlight an interaction between the anti-diabetic drugs and CaMKII expression/activity which requires further investigation. Together, the studies reviewed herein may guide pharmacological approaches to improve health-related outcomes in patients with diabetes.
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Affiliation(s)
- Stephanie Chacar
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
- Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates.
| | - Abdulhamid Abdi
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Khalifa Almansoori
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Jawaher Alshamsi
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Cynthia Al Hageh
- Department of Molecular Biology and Genetics, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Pierre Zalloua
- Department of Molecular Biology and Genetics, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates
| | - Ali A Khraibi
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates
| | - Stephen G Holt
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- SEHA Kidney Care, SEHA, Abu Dhabi, UAE
| | - Moni Nader
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
- Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates.
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10
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Xu W, Liu H. Is CaMKII friend or foe for cell apoptosis in eye?: A narrative review. Medicine (Baltimore) 2023; 102:e36136. [PMID: 38050317 PMCID: PMC10695602 DOI: 10.1097/md.0000000000036136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/25/2023] [Indexed: 12/06/2023] Open
Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) controls cell proliferation, differentiation, apoptosis, and other biological processes that have an essential role in eye diseases. However, it seems that previous studies have generated conflicting conclusions about the effect of CaMKII on cell apoptosis. In this review, we explore the positive and potentially deleterious effects of CaMKII on eye cell apoptosis. We can safely conclude that the early elevation of CaMKII could be viewed as a promoter of cell apoptosis. Overexpression of CaMKII by transfection or pretreatment with drugs helped combat cell apoptosis.
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Affiliation(s)
- Weixing Xu
- School of Graduate, Dalian Medical University, Dalian, China
- The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Hua Liu
- School of Graduate, Dalian Medical University, Dalian, China
- School of Graduate, Jinzhou Medical University, Jinzhou, China
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11
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Zhang W, Dong E, Zhang J, Zhang Y. CaMKII, 'jack of all trades' in inflammation during cardiac ischemia/reperfusion injury. J Mol Cell Cardiol 2023; 184:48-60. [PMID: 37813179 DOI: 10.1016/j.yjmcc.2023.10.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/11/2023]
Abstract
Myocardial infarction and revascularization cause cardiac ischemia/reperfusion (I/R) injury featuring cardiomyocyte death and inflammation. The Ca2+/calmodulin dependent protein kinase II (CaMKII) family are serine/ threonine protein kinases that are involved in I/R injury. CaMKII exists in four different isoforms, α, β, γ, and δ. In the heart, CaMKII-δ is the predominant isoform，with multiple splicing variants, such as δB, δC and δ9. During I/R, elevated intracellular Ca2+ concentrations and reactive oxygen species activate CaMKII. In this review, we summarized the regulation and function of CaMKII in multiple cell types including cardiomyocytes, endothelial cells, and macrophages during I/R. We conclude that CaMKII mediates inflammation in the microenvironment of the myocardium, resulting in cell dysfunction, elevated inflammation, and cell death. However, different CaMKII-δ variants exhibit distinct or even opposite functions. Therefore, reagents/approaches that selectively target specific CaMKII isoforms and variants are needed for evaluating and counteracting the exact role of CaMKII in I/R injury and developing effective treatments against I/R injury.
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Affiliation(s)
- Wenjia Zhang
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China
| | - Erdan Dong
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China; Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Junxia Zhang
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China; Haihe Laboratory of Cell Ecosystem, Beijing 100191, China.
| | - Yan Zhang
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
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12
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Elgendy SA, Soliman MM, Ghamry HI, Shukry M, Mohammed LA, Nasr HE, Alotaibi BS, Jafri I, Sayed S, Osman A, Elnoury HA. Exploration of Tilmicosin Cardiotoxicity in Rats and the Protecting Role of the Rhodiola rosea Extract: Potential Roles of Cytokines, Antioxidant, Apoptotic, and Anti-Fibrotic Pathways. TOXICS 2023; 11:857. [PMID: 37888707 PMCID: PMC10610616 DOI: 10.3390/toxics11100857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/18/2023] [Accepted: 09/20/2023] [Indexed: 10/28/2023]
Abstract
Tilmicosin (TIL) is a common macrolide antibiotic in veterinary medicine. High doses of TIL can have adverse cardiovascular effects. This study examined the effects of Rhodiola rosea (RHO) that have anti-inflammatory, antioxidant, and anti-fibrotic effects on tilmicosin (TIL)-induced cardiac injury targeting anti-inflammatory, antioxidant, apoptotic, and anti-apoptotic signaling pathways with anti-fibrotic outcomes. Thirty-six male Wistar albino rats were randomly divided into groups of six rats each. Rats received saline as a negative control, CARV 1 mL orally (10 mg/kg BW), and RHO 1 mL orally at 400 mg/kg BW daily for 12 consecutive days. The TIL group once received a single subcutaneous injection (SC) dose of TIL (75 mg/kg BW) on the sixth day of the experiment to induce cardiac damage. The standard group (CARV + TIL) received CARV daily for 12 consecutive days with a single TIL SC injection 1 h after CARV administration only on the sixth day of study and continued for another six successive days on CARV. The protective group (RHO + TIL) received RHO daily for the same period as in CARV + TIL-treated rats and with the dosage mentioned before. Serum was extracted at the time of the rat's scarification at 13 days of study and examined for biochemical assessments in serum lactate dehydrogenase (LDH), cardiac troponin I (cTI), and creatine phosphokinase (CK-MB). Protein carbonyl (PC) contents, malondialdehyde (MDA), and total antioxidant capacity (TAC) in cardiac homogenate were used to measure these oxidative stress markers. Quantitative RT-PCR was used to express interferon-gamma (INF-γ), cyclooxygenase-2 (COX-2), OGG1, BAX, caspase-3, B-cell lymphoma-2 (Bcl-2), and superoxide dismutase (SOD) genes in cardiac tissues, which are correlated with inflammation, antioxidants, and apoptosis. Alpha-smooth muscle actin (α-SMA), calmodulin (CaMKII), and other genes associated with Ca2+ hemostasis and fibrosis were examined using IHC analysis in cardiac cells (myocardium). TIL administration significantly increased the examined cardiac markers, LDH, cTI, and CK-MB. TIL administration also increased ROS, PC, and MDA while decreasing antioxidant activities (TAC and SOD mRNA) in cardiac tissues. Serum inflammatory cytokines and genes of inflammatory markers, DNA damage (INF-γ, COX-2), and apoptotic genes (caspase-3 and BAX) were upregulated with downregulation of the anti-apoptotic gene Bcl-2 as well as the DNA repair OGG1 in cardiac tissues. Furthermore, CaMKII and α-SMA genes were upregulated at cellular levels using cardiac tissue IHC analysis. On the contrary, pretreatment with RHO and CARV alone significantly decreased the cardiac injury markers induced by TIL, inflammatory and anti-inflammatory cytokines, and tissue oxidative-antioxidant parameters. INF-γ, COX-2, OGG1, BAX, and caspase-3 mRNA were downregulated, as observed by real-time PCR, while SOD and Bcl-2 mRNA were upregulated. Furthermore, the CaMKII and α-SMA genes' immune reactivities were significantly decreased in the RHO-pretreated rats.
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Affiliation(s)
- Salwa A. Elgendy
- Department of Pharmacology, Faculty of Medicine, Benha University, Benha 13511, Egypt
| | - Mohamed Mohamed Soliman
- Department of Clinical Laboratory Sciences, Turabah University College, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
- Biochemistry Department, Faculty of Veterinary Medicine, Benha University, Toukh 13736, Egypt
| | - Heba I. Ghamry
- Nutrition and Food Science, Department of Home Economics, Faculty of Home Economics, King Khalid University, P.O. Box 960, Abha 61421, Saudi Arabia;
| | - Mustafa Shukry
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Lina Abdelhady Mohammed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha 13511, Egypt (H.E.N.)
| | - Hend Elsayed Nasr
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha 13511, Egypt (H.E.N.)
| | - Badriyah S. Alotaibi
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Ibrahim Jafri
- Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Samy Sayed
- Department of Economic Entomology and Pesticides, Faculty of Agriculture, Cairo University, Giza 12613, Egypt;
- Department of Science and Technology, University College-Ranyah, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Amira Osman
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan;
- Department of Histology and Cell Biology, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Heba A. Elnoury
- Department of Pharmacology, Faculty of Medicine, Benha University, Benha 13511, Egypt
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Sun X, Cao J, Chen Z, Liu Y, VonCannon JL, Cheng HJ, Ferrario CM, Cheng CP. Increased CaMKII activation and contrast changes of cardiac β1-and β3-Adrenergic signaling pathways in a humanized angiotensinogen model of hypertension. Heliyon 2023; 9:e17851. [PMID: 37456012 PMCID: PMC10344767 DOI: 10.1016/j.heliyon.2023.e17851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/26/2023] [Accepted: 06/29/2023] [Indexed: 07/18/2023] Open
Abstract
Aims Upregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) contributes to the pathogenesis of cardiovascular disease, including hypertension. Transgenic rats expressing the human angiotensinogen gene [TGR (hAGT)L1623] are a new novel humanized model of hypertension that associates with declines in cardiac contractile function and β-adrenergic receptor (AR) reserve. The molecular mechanisms are unclear. We tested the hypothesis that in TGR (hAGT)L1623 rats, left ventricular (LV) myocyte CaMKIIδ and β3-AR are upregulated, but β1-AR is down-regulated, which are important causes of cardiac dysfunction and β-AR desensitization. Main methods We compared LV myocyte CaMKIIδ, CaMKIIδ phosphorylation (at Thr287) (pCaMKIIδ), and β1-and β3-AR expressions and determined myocyte functional and [Ca2+]I transient ([Ca2+]iT) responses to β-AR stimulation with and without pretreatment of myocytes using an inhibitor of CaMKII, KN-93 (10-6 M, 30 min) in male Sprague Dawley (SD; N = 10) control and TGR (hAGT)L1623 (N = 10) adult rats. Key findings Hypertension in TGR (hAGT)L1623 rats was accompanied by significantly increased LV myocyte β3-AR protein levels and reduced β1-AR protein levels. CaMKIIδ phosphorylation (at Thr287), pCaMKIIδ was significantly increased by 35%. These changes were followed by significantly reduced basal cell contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca2+]iT. Isoproterenol (10-8 M) produced significantly smaller increases in dL/dtmax, dR/dtmax, and [Ca2+]iT. Moreover, only in TGR (hAGT)L1623 rats, pretreatment of LV myocytes with KN-93 (10-6 M, 30 min) fully restored normal basal and isoproterenol-stimulated myocyte contraction, relaxation, and [Ca2+]iT. Significance LV myocyte CaMKIIδ overactivation with associated contrast changes in β3-AR and β1-AR may be the key molecular mechanism for the abnormal contractile phenotype and β-AR desensitization in this humanized model of hypertension.
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Affiliation(s)
- Xiaoqiang Sun
- Department of Cardiology, Tianjin First Central Hospital, Tianjin, China
- School of Medicine, Nankai University, Tianjin, China
- Department of Internal Medicine, Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jing Cao
- Department of Critical Care Medicine, First Hospital of Shanxi Medical University, Taiyuan, China
- Department of Internal Medicine, Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Zhe Chen
- Department of Internal Medicine, Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yixi Liu
- Department of Internal Medicine, Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Cardiology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jessica L. VonCannon
- Department of Surgery, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Heng Jie Cheng
- Department of Internal Medicine, Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Carlos M. Ferrario
- Department of Surgery, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Che Ping Cheng
- Department of Internal Medicine, Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
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Deb A, Tow BD, Qing Y, Walker M, Hodges ER, Stewart JA, Knollmann BC, Zheng Y, Wang Y, Liu B. Genetic Inhibition of Mitochondrial Permeability Transition Pore Exacerbates Ryanodine Receptor 2 Dysfunction in Arrhythmic Disease. Cells 2023; 12:204. [PMID: 36672139 PMCID: PMC9856515 DOI: 10.3390/cells12020204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/12/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). We hypothesize that inhibiting the mPTP opening in CPVT exacerbates the disease phenotype. By crossbreeding a CPVT model of CASQ2 knockout (KO) with a mouse missing CypD, an activator of mPTP, a double KO model (DKO) was generated. Echocardiography, cardiac histology, and live-cell imaging were employed to assess the severity of cardiac pathology. Western blot and RNAseq were performed to evaluate the contribution of various signaling pathways. Although exacerbated arrhythmias were reported, the DKO model did not exhibit pathological remodeling. Myocyte Ca2+ handling was similar to that of the CASQ2 KO mouse at a low pacing frequency. However, increased ROS production, activation of the CaMKII pathway, and hyperphosphorylation of RyR2 were detected in DKO. Transcriptome analysis identified altered gene expression profiles associated with electrical instability in DKO. Our study provides evidence that genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2.
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Affiliation(s)
- Arpita Deb
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
| | - Brian D. Tow
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
| | - You Qing
- Beijing Key Laboratory for Agricultural Application and New Technique, College of Plant Science and Technology, Bioinformatics Center, Beijing University of Agriculture, Beijing 102206, China
| | - Madelyn Walker
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
| | - Emmanuel R. Hodges
- School of Pharmacy, Division of BioMolecular Sciences, University of Mississippi, Oxford, MS 38677, USA
| | - James A. Stewart
- School of Pharmacy, Division of BioMolecular Sciences, University of Mississippi, Oxford, MS 38677, USA
| | - Björn C. Knollmann
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Yi Zheng
- Beijing Key Laboratory for Agricultural Application and New Technique, College of Plant Science and Technology, Bioinformatics Center, Beijing University of Agriculture, Beijing 102206, China
| | - Ying Wang
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
| | - Bin Liu
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
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15
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Calmodulin-dependent protein kinase II activation promotes kidney mesangial expansion in streptozotocin-induced diabetic mice. Heliyon 2022; 8:e11653. [DOI: 10.1016/j.heliyon.2022.e11653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/30/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
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Qi Y, Xu H, Li X, Zhao X, Li Y, Zhou X, Chen S, Shen N, Chen R, Li Y, Sun Z, Guo C. Silica nanoparticles induce cardiac injury and dysfunction via ROS/Ca 2+/CaMKII signaling. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 837:155733. [PMID: 35526619 DOI: 10.1016/j.scitotenv.2022.155733] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 06/14/2023]
Abstract
Interest is growing to better comprehend the interaction of silica nanoparticles (SiNPs) with the cardiovascular system. In particular, the extremely small size, relatively large surface area and associated unique properties may greatly enhance its toxic potentials compared to larger-sized counterparts. Nevertheless, the underlying mechanisms still need to be evaluated. In this context, the cardiotoxicity of nano-scale (Si-60; particle diameter about 60 nm) and submicro-scale silica particles (Si-300; 300 nm) were examined in ApoE-/- mice via intratracheal instillation, 6.0 mg/kg·bw, once per week for 12 times. The echocardiography showed that the sub-chronic exposure of Si-60 declined cardiac output (CO) and stroke volume (SV), shorten LVIDd and LVIDs, and thickened LVAWs of ApoE-/- mice in compared to the control and Si-300 groups. Histological investigations manifested Si-60 enhanced inflammatory infiltration, myocardial fiber arrangement disorder, hypertrophy and fibrosis in the cardiac tissue, as well as mitochondrial ultrastructural injury. Accordingly, the serum cTnT, cTnI and ANP were significantly elevated by Si-60, as well as cardiac ANP content. In particular, Si-60 greatly increased cardiac ROS, Ca2+ levels and CaMKII activation in comparison with Si-300. Further, in vitro investigations revealed silica particles induced a dose- and size-dependent activation of oxidative stress, mitochondrial membrane permeabilization, intracellular Ca2+ overload, CaMKII signaling activation and ensuing myocardial apoptosis in human cardiomyocytes (AC16). Mechanistic analyses revealed SiNPs induced myocardial apoptosis via ROS/Ca2+/CaMKII signaling, which may contribute to the abnormalities in cardiac structure and function in vivo. In summary, our research revealed SiNPs caused myocardial impairments, dysfunction and even structural remodeling via ROS/Ca2+/CaMKII signaling. Of note, a size-dependent myocardial toxicity was noticed, that is, Si-60 greater than Si-300.
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Affiliation(s)
- Yi Qi
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Hailin Xu
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Xueyan Li
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Xinying Zhao
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Yan Li
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Xianqing Zhou
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Siyu Chen
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Ning Shen
- Nantong Fourth People's Hospital, Kangda College of Nanjing Medical University Affiliated Nantong Mental Health Centre, Nantong 226005, China; China Exposomics Institute (CEI) Precision Medicine Co. Ltd, Shanghai 200120, China
| | - Rui Chen
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Yanbo Li
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China.
| | - Zhiwei Sun
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Caixia Guo
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
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17
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Wu J, Liu Y, Wei X, Zhang X, Ye Y, Li W, Su X. Antiarrhythmic effects and mechanisms of sodium-glucose cotransporter 2 inhibitors: A mini review. Front Cardiovasc Med 2022; 9:915455. [PMID: 36003915 PMCID: PMC9393294 DOI: 10.3389/fcvm.2022.915455] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/14/2022] [Indexed: 11/13/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new type of oral hypoglycaemic agent with good cardiovascular protective effects. There are several lines of clinical evidence suggest that SGLT2i can significantly reduce the risks of heart failure, cardiovascular death, and delay the progression of chronic kidney disease. In addition, recent basic and clinical studies have also reported that SGLT2i also has good anti-arrhythmic effects. However, the exact mechanism is poorly understood. The aim of this review is to summarize recent clinical findings, studies of laboratory animals, and related study about this aspect of the antiarrhythmic effects of SGLT2i, to further explore its underlying mechanisms, safety, and prospects for clinical applications of it.
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Affiliation(s)
- Jinchun Wu
- Department of Cardiology, Qinghai Provincial People's Hospital, Xining, China
- *Correspondence: Jinchun Wu
| | - Yanmin Liu
- Department of Cardiology, Qinghai Provincial People's Hospital, Xining, China
| | - Xiaojuan Wei
- Department of Cardiology, Qinghai Provincial People's Hospital, Xining, China
| | - Xiaofei Zhang
- Department of Cardiology, Qinghai Provincial People's Hospital, Xining, China
| | - Yi Ye
- Graduate School of Qinghai University, Qinghai University, Xining, China
| | - Wei Li
- Department of Cardiology, Qinghai Provincial People's Hospital, Xining, China
| | - Xiaoling Su
- Department of Cardiology, Qinghai Provincial People's Hospital, Xining, China
- Xiaoling Su
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18
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Roberts-Craig FT, Worthington LP, O’Hara SP, Erickson JR, Heather AK, Ashley Z. CaMKII Splice Variants in Vascular Smooth Muscle Cells: The Next Step or Redundancy? Int J Mol Sci 2022; 23:ijms23147916. [PMID: 35887264 PMCID: PMC9318135 DOI: 10.3390/ijms23147916] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 02/05/2023] Open
Abstract
Vascular smooth muscle cells (VSMCs) help to maintain the normal physiological contractility of arterial vessels to control blood pressure; they can also contribute to vascular disease such as atherosclerosis. Ca2+/calmodulin-dependent kinase II (CaMKII), a multifunctional enzyme with four isoforms and multiple alternative splice variants, contributes to numerous functions within VSMCs. The role of these isoforms has been widely studied across numerous tissue types; however, their functions are still largely unknown within the vasculature. Even more understudied is the role of the different splice variants of each isoform in such signaling pathways. This review evaluates the role of the different CaMKII splice variants in vascular pathological and physiological mechanisms, aiming to show the need for more research to highlight both the deleterious and protective functions of the various splice variants.
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Affiliation(s)
- Finn T. Roberts-Craig
- Department of Medicine, University of Otago, Dunedin 9016, New Zealand;
- Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand; (L.P.W.); (S.P.O.); (J.R.E.); (A.K.H.)
| | - Luke P. Worthington
- Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand; (L.P.W.); (S.P.O.); (J.R.E.); (A.K.H.)
- HeartOtago, University of Otago, Dunedin 9016, New Zealand
| | - Samuel P. O’Hara
- Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand; (L.P.W.); (S.P.O.); (J.R.E.); (A.K.H.)
- HeartOtago, University of Otago, Dunedin 9016, New Zealand
| | - Jeffrey R. Erickson
- Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand; (L.P.W.); (S.P.O.); (J.R.E.); (A.K.H.)
- HeartOtago, University of Otago, Dunedin 9016, New Zealand
| | - Alison K. Heather
- Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand; (L.P.W.); (S.P.O.); (J.R.E.); (A.K.H.)
- HeartOtago, University of Otago, Dunedin 9016, New Zealand
| | - Zoe Ashley
- Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand; (L.P.W.); (S.P.O.); (J.R.E.); (A.K.H.)
- HeartOtago, University of Otago, Dunedin 9016, New Zealand
- Correspondence: ; Tel.: +64-3-479-7646
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19
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Glutamate drives 'local Ca 2+ release' in cardiac pacemaker cells. Cell Res 2022; 32:843-854. [PMID: 35840807 PMCID: PMC9437105 DOI: 10.1038/s41422-022-00693-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 06/27/2022] [Indexed: 11/30/2022] Open
Abstract
The sinoatrial node (SAN) is the origin of the electrical signals for rhythmic heartbeats in mammals. The spontaneous firing of SAN pacemaker cells (SANPCs) triggers cardiac contraction. ‘Local Ca2+ release’ (LCR), a unique cellular activity, acts as the ‘engine’ of the spontaneous firing of SANPCs. However, the mechanism of LCR initiation remains unclear. Here, we report that endogenous glutamate drives LCRs in SANPCs. Using a glutamate sensor, we unraveled a tight correlation between glutamate accumulation and LCR occurrence, indicating a potential relationship between glutamate and LCRs. Intracellular application of glutamate significantly enhanced the LCRs in both intact and permeabilized SANPCs. Mechanistically, we revealed that mitochondrial excitatory amino acid transporter 1 (EAAT1)-dependent mitochondrial glutamate import promoted ROS generation, which in turn led to the oxidation of Ca2+-handling proteins, ultimately resulting in enhanced LCRs. Importantly, EAAT1 depletion reduced both the spontaneous firing rates of isolated SANPCs and the heart rate in vitro and in vivo, suggesting the central role of EAAT1 as a glutamate transporter in the regulation of cardiac autonomic rhythm. In conclusion, our results indicate that glutamate serves as an LCR igniter in SANPCs, adding a potentially important element to the coupled-clock theory that explains the origin of spontaneous firing. These findings shed new light on the future prevention and treatment of cardiac pacemaker cell-related arrhythmias.
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20
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Lazzarini E, Lodrini AM, Arici M, Bolis S, Vagni S, Panella S, Rendon-Angel A, Saibene M, Metallo A, Torre T, Vassalli G, Ameri P, Altomare C, Rocchetti M, Barile L. Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging. Theranostics 2022; 12:5237-5257. [PMID: 35836799 PMCID: PMC9274748 DOI: 10.7150/thno.70884] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 06/11/2022] [Indexed: 01/12/2023] Open
Abstract
Rationale: Aging in the heart is a gradual process, involving continuous changes in cardiovascular cells, including cardiomyocytes (CMs), namely cellular senescence. These changes finally lead to adverse organ remodeling and resulting in heart failure. This study exploits CMs from human induced pluripotent stem cells (iCMs) as a tool to model and characterize mechanisms involved in aging. Methods and Results: Human somatic cells were reprogrammed into human induced pluripotent stem cells and subsequently differentiated in iCMs. A senescent-like phenotype (SenCMs) was induced by short exposure (3 hours) to doxorubicin (Dox) at the sub-lethal concentration of 0.2 µM. Dox treatment induced expression of cyclin-dependent kinase inhibitors p21 and p16, and increased positivity to senescence-associated beta-galactosidase when compared to untreated iCMs. SenCMs showed increased oxidative stress, alteration in mitochondrial morphology and depolarized mitochondrial membrane potential, which resulted in decreased ATP production. Functionally, when compared to iCMs, SenCMs showed, prolonged multicellular QTc and single cell APD, with increased APD variability and delayed afterdepolarizations (DADs) incidence, two well-known arrhythmogenic indexes. These effects were largely ascribable to augmented late sodium current (INaL) and reduced delayed rectifier potassium current (Ikr). Moreover sarcoplasmic reticulum (SR) Ca2+ content was reduced because of downregulated SERCA2 and increased RyR2-mediated Ca2+ leak. Electrical and intracellular Ca2+ alterations were mostly justified by increased CaMKII activity in SenCMs. Finally, SenCMs phenotype was furtherly confirmed by analyzing physiological aging in CMs isolated from old mice in comparison to young ones. Conclusions: Overall, we showed that SenCMs recapitulate the phenotype of aged primary CMs in terms of senescence markers, electrical and Ca2+ handling properties and metabolic features. Thus, Dox-induced SenCMs can be considered a novel in vitro platform to study aging mechanisms and to envision cardiac specific anti-aging approach in humans.
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Affiliation(s)
- Edoardo Lazzarini
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Alessandra Maria Lodrini
- Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca, Milano, Italy.,Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Martina Arici
- Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca, Milano, Italy
| | - Sara Bolis
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.,Cellular and Molecular Cardiology, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Sara Vagni
- Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca, Milano, Italy
| | - Stefano Panella
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Azucena Rendon-Angel
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.,Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - Melissa Saibene
- Department of Earth and Environmental Sciences, Università degli Studi di Milano-Bicocca, Milano, Italy
| | - Alessia Metallo
- Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca, Milano, Italy
| | - Tiziano Torre
- Department of Cardiac Surgery Istituto Cardiocentro Ticino, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Giuseppe Vassalli
- Cellular and Molecular Cardiology, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.,Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - Pietro Ameri
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico, Genova, Italy.,Department of Internal Medicine, University of Genova, Genova, Italy
| | - Claudia Altomare
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Marcella Rocchetti
- Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca, Milano, Italy.,✉ Corresponding authors: Lucio Barile, PhD. Istituto Cardiocentro Ticino, Laboratories for Translational Research, EOC Via Chiesa 5, 6500 Bellinzona, Switzerland. +41 586667104 ; Marcella Rocchetti, PhD. University of Milano-Bicocca, Dept. of Biotechnology and Biosciences, P.za della Scienza 2, 20126 Milano, Italy. +39 0264483313
| | - Lucio Barile
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.,Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.,Institute of Life Science, Scuola Superiore Sant'Anna, Pisa, Italy.,✉ Corresponding authors: Lucio Barile, PhD. Istituto Cardiocentro Ticino, Laboratories for Translational Research, EOC Via Chiesa 5, 6500 Bellinzona, Switzerland. +41 586667104 ; Marcella Rocchetti, PhD. University of Milano-Bicocca, Dept. of Biotechnology and Biosciences, P.za della Scienza 2, 20126 Milano, Italy. +39 0264483313
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21
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Kim BH, Jung JW, Han D, Cha MJ, Chang JH. One-Week Dynamic Changes in Cardiac Proteomes After Cardiac Radioablation in Experimental Rat Model. Front Cardiovasc Med 2022; 9:898222. [PMID: 35837601 PMCID: PMC9273889 DOI: 10.3389/fcvm.2022.898222] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/06/2022] [Indexed: 11/28/2022] Open
Abstract
Background Recently, stereotactic ablative radiotherapy (SABR) has been adopted to non-invasively treat catheter ablation-refractory ventricular tachycardia (VT). VT episodes have been dramatically reduced after SABR, within weeks; however the underlying mechanisms of these clinical effects and potential mediators of early anti-arrhythmic effect remain unclear. Methods In this study, cardiac tissue was harvested from non-irradiated control (0 Gy), conventional irradiated control (2 Gy), and radioablative test (25 Gy) rat groups after 3 and 7 days of irradiation. The samples were proteomically analyzed to identify the differentially expressed proteins (DEP) between different groups. Validation experiments were performed similar to validation in profiling where Data independent acquisition and parallel reaction monitoring methods were used. Data are available via ProteomeXchange with identifier PXD030878. Results Functional enrichment analysis of 25 Gy sample showed that among the downregulated proteins, "intracellular signal transduction" and "cell to cell adhesion" proteins were significantly affected at day 3 while "Ras protein signal transduction," "GTPase regulation," and "actin filament-based process" proteins were majorly affected at day 7. GO analysis demonstrated that most of the upregulated proteins belonged to the classes "cellular stress response," "endomembranal organization," or "endoplasmic reticulum stress response" at day 3. At day 7, 42 proteins, mainly associated with response to drug, organic substance, or radiation, were specifically upregulated in 25 Gy. DEP analysis of cardiac conduction showed Ryr2 and Cav1 upregulation and Cacna2d2, Gja3, Scnb2, and Kcnn3 downregulation in the 25 Gy group compared to 0 Gy. In validation experiments, four proteins (Gsta1, Myot, Ephx1, and Capg) were repeatedly detected with 25 Gy-specific patterns at day 7. Conclusions 25 Gy single fractional irradiation induces considerable cardiac proteome changes within the first 7 days, distinct from 2 Gy. Several candidate proteins displayed 25 Gy-specific changes and were related to oxidative stress-induced innate response or cardiac remodeling processes. Future studies should explore the specific role of these proteins upon cardiac radioablation.
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Affiliation(s)
- Byoung Hyuck Kim
- Department of Radiation Oncology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, South Korea
| | - Jin Woo Jung
- Proteomics Core Facility, Transdisciplinary Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Dohyun Han
- Proteomics Core Facility, Transdisciplinary Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
- Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, South Korea
| | - Myung-Jin Cha
- Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji Hyun Chang
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, South Korea
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22
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Hu Q, Chen H, Shen C, Zhang B, Weng X, Sun X, Liu J, Dong Z, Hu K, Ge J, Sun A. Impact and potential mechanism of effects of chronic moderate alcohol consumption on cardiac function in aldehyde dehydrogenase 2 gene heterozygous mice. Alcohol Clin Exp Res 2022; 46:707-723. [PMID: 35315077 PMCID: PMC9321750 DOI: 10.1111/acer.14811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 03/12/2022] [Accepted: 03/16/2022] [Indexed: 12/01/2022]
Abstract
Background Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism. The ALDH2*2 mutations are found in approximately 45% of East Asians, with 40% being heterozygous (HE) ALDH2*1/*2 and 5% homozygous (HO) ALDH2*2/*2. Studies have shown that HO mice lack cardioprotective effects induced by moderate alcohol consumption. However, the impact of moderate alcohol consumption on cardiac function in HE mice is unknown. Methods In this study, HO, HE, and wild‐type (WT) mice were subjected to a 6‐week moderate alcohol drinking protocol, following which myocardial tissue and cardiomyocytes of the mice were extracted. Results We found that moderate alcohol exposure did not increase mortality, myocardial fibrosis, apoptosis, or inflammation in HE mice, which differs from the effects observed in HO mice. After exposure to the 6‐week alcohol drinking protocol, there was impaired cardiac function, cardiomyocyte contractility, and intracellular Ca2+ homeostasis and mitochondrial function in both HE and HO mice as compared to WT mice. Moreover, these animals showed overt oxidative stress production and increased levels of the activated forms of calmodulin‐dependent protein kinase II (CaMKII) and ryanodine receptor type 2 (RYR2) phosphorylation protein. Conclusion We found that moderate alcohol exposure impaired cardiac function in HE mice, possibly by increasing reactive oxygen species (ROS)/CaMKII/RYR2‐mediated Ca2+ handling abnormalities. Hence, we advocate that people with ALDH2*1/*2 genotypes rigorously avoid alcohol consumption to prevent potential cardiovascular harm induced by moderate alcohol consumption.
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Affiliation(s)
- Qinfeng Hu
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Hang Chen
- Heart Center of Fujian Province, Union Hospital, Fujian Medical University, Fuzhou, China.,Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Shen
- Department of Cardiology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Beijian Zhang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Viral Heart Diseases, Shanghai, China.,Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Xinyu Weng
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Viral Heart Diseases, Shanghai, China.,Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Xiaolei Sun
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Viral Heart Diseases, Shanghai, China.,Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Jin Liu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Viral Heart Diseases, Shanghai, China.,Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Zhen Dong
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Viral Heart Diseases, Shanghai, China.,Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Kai Hu
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Junbo Ge
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Viral Heart Diseases, Shanghai, China.,Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Aijun Sun
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Viral Heart Diseases, Shanghai, China.,Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China
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23
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Zhang J, Liang R, Wang K, Zhang W, Zhang M, Jin L, Xie P, Zheng W, Shang H, Hu Q, Li J, Chen G, Wu F, Lan F, Wang L, Wang SQ, Li Y, Zhang Y, Liu J, Lv F, Hu X, Xiao RP, Lei X, Zhang Y. Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth. Circulation 2022; 145:1154-1168. [PMID: 35317609 DOI: 10.1161/circulationaha.121.055920] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 01/07/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease, the leading cause of morbidity and mortality worldwide. At present, there is no effective therapy for reducing cardiac I/R injury. CaMKII (Ca2+/calmodulin-dependent kinase II) plays a pivotal role in the pathogenesis of severe heart conditions, including I/R injury. Pharmacological inhibition of CaMKII is an important strategy in the protection against myocardial damage and cardiac diseases. To date, there is no drug targeting CaMKII for the clinical therapy of heart disease. Furthermore, at present, there is no selective inhibitor of CaMKII-δ, the major CaMKII isoform in the heart. METHODS A small-molecule kinase inhibitor library and a high-throughput screening system for the kinase activity assay of CaMKII-δ9 (the most abundant CaMKII-δ splice variant in human heart) were used to screen for CaMKII-δ inhibitors. Using cultured neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse models, in conjunction with myocardial injury induced by I/R (or hypoxia/reoxygenation) and CaMKII-δ9 overexpression, we sought to investigate the protection of hesperadin against cardiomyocyte death and cardiac diseases. BALB/c nude mice with xenografted tumors of human cancer cells were used to evaluate the in vivo antitumor effect of hesperadin. RESULTS Based on the small-molecule kinase inhibitor library and screening system, we found that hesperadin, an Aurora B kinase inhibitor with antitumor activity in vitro, directly bound to CaMKII-δ and specifically blocked its activation in an ATP-competitive manner. Hesperadin functionally ameliorated both I/R- and overexpressed CaMKII-δ9-induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell-derived cardiomyocytes. In addition, in an in vivo BALB/c nude mouse model with xenografted tumors of human cancer cells, hesperadin delayed tumor growth without inducing cardiomyocyte death or cardiac injury. CONCLUSIONS Here, we identified hesperadin as a specific small-molecule inhibitor of CaMKII-δ with dual functions of cardioprotective and antitumor effects. These findings not only suggest that hesperadin is a promising leading compound for clinical therapy of cardiac I/R injury and heart failure, but also provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anticancer treatment.
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Affiliation(s)
- Junxia Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Ruqi Liang
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering (R.L., X.L.), Peking University, Beijing, China
| | - Kai Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Ministry of Education, Beijing, China (K.W.)
| | - Wenjia Zhang
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education (W. Zhang, Yan Zhang), Peking University Health Science Center, Beijing, China
| | - Mao Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Li Jin
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Peng Xie
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Wen Zheng
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Haibao Shang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Qingmei Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Jiayi Li
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Gengjia Chen
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Fujian Wu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (F.W., F.L.)
| | - Feng Lan
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (F.W., F.L.)
| | - Lipeng Wang
- College of Life Sciences (L.W., S.-Q.W.), Peking University, Beijing, China
| | - Shi-Qiang Wang
- College of Life Sciences (L.W., S.-Q.W.), Peking University, Beijing, China
| | - Yongfeng Li
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences (Y.L., Yong Zhang), Peking University Health Science Center, Beijing, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, IDG/McGovern Institute for Brain Research at PKU. Beijing, China (Y.L., Yong Zhang)
| | - Yong Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education (W. Zhang, Yan Zhang), Peking University Health Science Center, Beijing, China
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences (Y.L., Yong Zhang), Peking University Health Science Center, Beijing, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, IDG/McGovern Institute for Brain Research at PKU. Beijing, China (Y.L., Yong Zhang)
| | - Jinghao Liu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Fengxiang Lv
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Xinli Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
| | - Rui-Ping Xiao
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences (R.-P.X., X.L.), Peking University, Beijing, China
- Beijing City Key Laboratory of Cardiometabolic Molecular Medicine (R.-P.X.), Peking University, Beijing, China
- PKU-Nanjing Joint Institute of Translational Medicine, Nanjing, China (R.-P.X.)
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering (R.L., X.L.), Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences (R.-P.X., X.L.), Peking University, Beijing, China
- Academy for Advanced Interdisciplinary Studies (X.L.), Peking University, Beijing, China
| | - Yan Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (J.Z., M.Z., L.J., P.X., W. Zheng, H.S., Q.H., J. Li, G.C., J. Liu, F.L., X.H., R.-P.X., Yan Zhang), Peking University, Beijing, China
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Yao Y, Li F, Zhang M, Jin L, Xie P, Liu D, Zhang J, Hu X, Lv F, Shang H, Zheng W, Sun X, Duanmu J, Wu F, Lan F, Xiao RP, Zhang Y. Targeting CaMKII-δ9 Ameliorates Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Inflammation. Circ Res 2022; 130:887-903. [PMID: 35152717 DOI: 10.1161/circresaha.121.319478] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 02/01/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND CaMKII (Ca2+/calmodulin-dependent kinase II) plays a central role in cardiac ischemia/reperfusion (I/R) injury-an important therapeutic target for ischemic heart disease. In the heart, CaMKII-δ is the predominant isoform and further alternatively spliced into 11 variants. In humans, CaMKII-δ9 and CaMKII-δ3, the major cardiac splice variants, inversely regulate cardiomyocyte viability with the former pro-death and the latter pro-survival. However, it is unknown whether specific inhibition of the detrimental CaMKII-δ9 prevents cardiac I/R injury and, if so, what is the underlying mechanism. Here, we aim to investigate the cardioprotective effect of specific CaMKII-δ9 inhibition against myocardial I/R damage and determine the underlying mechanisms. METHODS The role and mechanism of CaMKII-δ9 in cardiac I/R injury were investigated in mice in vivo, neonatal rat ventricular myocytes, and human embryonic stem cell-derived cardiomyocytes. RESULTS We demonstrate that CaMKII-δ9 inhibition with knockdown or knockout of its feature exon, exon 16, protects the heart against I/R-elicited injury and subsequent heart failure. I/R-induced cardiac inflammation was also ameliorated by CaMKII-δ9 inhibition, and compared with the previously well-studied CaMKII-δ2, CaMKII-δ9 overexpression caused more profound cardiac inflammation. Mechanistically, in addition to IKKβ (inhibitor of NF-κB [nuclear factor-κB] kinase subunit β), CaMKII-δ9, but not δ2, directly interacted with IκBα (NF-κB inhibitor α) with its feature exon 13-16-17 combination and increased IκBα phosphorylation and consequently elicited more pronounced activation of NF-κB signaling and inflammatory response. Furthermore, the essential role of CaMKII-δ9 in myocardial inflammation and damage was confirmed in human cardiomyocytes. CONCLUSIONS We not only identified CaMKII-δ9-IKK/IκB-NF-κB signaling as a new regulator of human cardiomyocyte inflammation but also demonstrated that specifically targeting CaMKII-δ9, the most abundant CaMKII-δ splice variant in human heart, markedly suppresses I/R-induced cardiac NF-κB activation, inflammation, and injury and subsequently ameliorates myocardial remodeling and heart failure, providing a novel therapeutic strategy for various ischemic heart diseases.
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Affiliation(s)
- Yuan Yao
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Fan Li
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Mao Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Li Jin
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Peng Xie
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Dairu Liu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Junxia Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Xinli Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Fengxiang Lv
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Haibao Shang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Wen Zheng
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Xueting Sun
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
| | - Jiaxin Duanmu
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China (J.D., Y.Z.)
| | - Fujian Wu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (F.W., F. Lan)
| | - Feng Lan
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (F.W., F. Lan)
| | - Rui-Ping Xiao
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
- Beijing City Key Laboratory of Cardiometabolic Molecular Medicine (R.-P.X.), Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China (R.-P.X.)
- PKU-Nanjing Institute of Translational Medicine, China (R.-P.X.)
| | - Yan Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Y.Y., F. Li, M.Z., L.J., P.X., D.L., J.Z., X.H., F. Lv, H.S., W.Z., X.S., R.-P.X., Y.Z.), Peking University, Beijing, China
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China (J.D., Y.Z.)
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25
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Consumption of combined fructose and sucrose diet exacerbates oxidative stress, hypertrophy and CaMKII δ oxidation in hearts from rats with metabolic syndrome. Mol Cell Biochem 2022; 477:1309-1320. [PMID: 35138512 DOI: 10.1007/s11010-022-04364-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 01/12/2022] [Indexed: 10/19/2022]
Abstract
The prevalence of the metabolic syndrome (MetS) and its cardiac comorbidities as cardiac hypertrophy (CH) have increased considerably due to the high consumption of carbohydrates, such as sucrose and/or fructose. We compared the effects of sucrose (S), fructose (F) and their combination (S + F) on the development of MetS in weaned male Wistar rats and established the relationship between the consumption of these sugars and the degree of cardiac CH development, oxidative stress (OS) and Calcium/calmodulin-dependent protein kinase type II subunit delta oxidation (ox-CaMKIIδ). 12 weeks after the beginning of treatments with S, F or S + F, arterial pressure was measured and 8 weeks later (to complete 20 weeks) the animals were sacrificed and blood samples, visceral adipose tissue and hearts were obtained. Biochemical parameters were determined in serum and cardiac tissue to evaluate the development of MetS and OS. To evaluate CH, atrial natriuretic peptide (ANP), CaMKIIδ and ox-CaMKIIδ were determined by western blot and histological studies were performed in cardiac tissue. Our data showed that chronic consumption of S + F exacerbates MetS-induced CH which is related with a higher OS and ox-CaMKIIδ.
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26
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Role of ranolazine in heart failure: From cellular to clinic perspective. Eur J Pharmacol 2022; 919:174787. [PMID: 35114190 DOI: 10.1016/j.ejphar.2022.174787] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/25/2021] [Accepted: 01/25/2022] [Indexed: 12/17/2022]
Abstract
Ranolazine was approved by the US Food and Drug Administration as an antianginal drug in 2006, and has been used since in certain groups of patients with stable angina. The therapeutic action of ranolazine was initially attributed to inhibitory effects on fatty acids metabolism. As investigations went on, however, it developed that the main beneficial effects of ranolazine arise from its action on the late sodium current in the heart. Since late sodium currents were discovered to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure, ranolazine has in some way been tested either directly or indirectly on heart failure in numerous experimental and clinical studies. As the heart continuously remodels following any sort of severe injury, the inhibition by ranolazine of the underlying mechanisms of cardiac remodeling including ion disturbances, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal impairment are discussed, along with unresolved issues. A projection of pathologies targeted by ranolazine from cellular level to clinical is provided in this review.
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27
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Zhang M, Zhang J, Zhang W, Hu Q, Jin L, Xie P, Zheng W, Shang H, Zhang Y. CaMKII-δ9 Induces Cardiomyocyte Death to Promote Cardiomyopathy and Heart Failure. Front Cardiovasc Med 2022; 8:820416. [PMID: 35127874 PMCID: PMC8811042 DOI: 10.3389/fcvm.2021.820416] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/21/2021] [Indexed: 01/11/2023] Open
Abstract
Heart failure is a syndrome in which the heart cannot pump enough blood to meet the body's needs, resulting from impaired ventricular filling or ejection of blood. Heart failure is still a global public health problem and remains a substantial unmet medical need. Therefore, it is crucial to identify new therapeutic targets for heart failure. Ca2+/calmodulin-dependent kinase II (CaMKII) is a serine/threonine protein kinase that modulates various cardiac diseases. CaMKII-δ9 is the most abundant CaMKII-δ splice variant in the human heart and acts as a central mediator of DNA damage and cell death in cardiomyocytes. Here, we proved that CaMKII-δ9 mediated cardiomyocyte death promotes cardiomyopathy and heart failure. However, CaMKII-δ9 did not directly regulate cardiac hypertrophy. Furthermore, we also showed that CaMKII-δ9 induced cell death in adult cardiomyocytes through impairing the UBE2T/DNA repair signaling. Finally, we demonstrated no gender difference in the expression of CaMKII-δ9 in the hearts, together with its related cardiac pathology. These findings deepen our understanding of the role of CaMKII-δ9 in cardiac pathology and provide new insights into the mechanisms and therapy of heart failure.
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Affiliation(s)
- Mao Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
| | - Junxia Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Wenjia Zhang
- Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
| | - Qingmei Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Li Jin
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Peng Xie
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Wen Zheng
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Haibao Shang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Yan Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- *Correspondence: Yan Zhang
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28
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Multiscale Modeling of the Mitochondrial Origin of Cardiac Reentrant and Fibrillatory Arrhythmias. Methods Mol Biol 2022; 2399:247-259. [PMID: 35604560 PMCID: PMC10186263 DOI: 10.1007/978-1-0716-1831-8_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
While mitochondrial dysfunction has been implicated in the pathogenesis of cardiac arrhythmias, how the abnormality occurring at the organelle level escalates to influence the rhythm of the heart remains incompletely understood. This is due, in part, to the complexity of the interactions formed by cardiac electrical, mechanical, and metabolic subsystems at various spatiotemporal scales that is difficult to fully comprehend solely with experiments. Computational models have emerged as a powerful tool to explore complicated and highly dynamic biological systems such as the heart, alone or in combination with experimental measurements. Here, we describe a strategy of integrating computer simulations with optical mapping of cardiomyocyte monolayers to examine how regional mitochondrial dysfunction elicits abnormal electrical activity, such as rebound and spiral waves, leading to reentry and fibrillation in cardiac tissue. We anticipate that this advanced modeling technology will enable new insights into the mechanisms by which changes in subcellular organelles can impact organ function.
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29
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Koyani CN, Scheruebel S, Jin G, Kolesnik E, Zorn-Pauly K, Mächler H, Hoefler G, von Lewinski D, Heinzel FR, Pelzmann B, Malle E. Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes. Antioxidants (Basel) 2021; 11:25. [PMID: 35052529 PMCID: PMC8772905 DOI: 10.3390/antiox11010025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 02/05/2023] Open
Abstract
Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades in various cell types, in the human infarcted myocardium. We performed immunohistochemistry for MPO and HOCl-LDL in human myocardial tissue, investigated the impact of HOCl-LDL on electrophysiology and contractility in primary cardiomyocytes, and explored underlying mechanisms in HL-1 cardiomyocytes and human atrial appendages using immunoblot analysis, qPCR, and silencing experiments. HOCl-LDL reduced ICa,L and IK1, and increased INaL, leading to altered action potential characteristics and arrhythmic events including early- and delayed-afterdepolarizations. HOCl-LDL altered the expression and function of CaV1.2, RyR2, NCX1, and SERCA2a, resulting in impaired contractility and Ca2+ homeostasis. Elevated superoxide anion levels and oxidation of CaMKII were mediated via LOX-1 signaling in HL-1 cardiomyocytes. Furthermore, HOCl-LDL-mediated alterations of cardiac contractility and electrophysiology, including arrhythmic events, were ameliorated by the CaMKII inhibitor KN93 and the INaL blocker, ranolazine. This study provides an explanatory framework for the detrimental effects of HOCl-LDL compared to native LDL and cardiac remodeling in patients with high MPO levels during the progression of cardiovascular disease.
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Affiliation(s)
- Chintan N. Koyani
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria;
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, 8036 Graz, Austria; (G.J.); (E.K.); (D.v.L.)
| | - Susanne Scheruebel
- Division of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria; (S.S.); (K.Z.-P.)
| | - Ge Jin
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, 8036 Graz, Austria; (G.J.); (E.K.); (D.v.L.)
- The 2nd Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Ewald Kolesnik
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, 8036 Graz, Austria; (G.J.); (E.K.); (D.v.L.)
| | - Klaus Zorn-Pauly
- Division of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria; (S.S.); (K.Z.-P.)
| | - Heinrich Mächler
- Department of Surgery, Division of Cardiac Surgery, Medical University of Graz, 8036 Graz, Austria;
| | - Gerald Hoefler
- Diagnostic and Research Center for Molecular BioMedicine, Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria;
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, 8036 Graz, Austria; (G.J.); (E.K.); (D.v.L.)
| | - Frank R. Heinzel
- Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany;
- Deutsches Zentrum für Herz-Kreislauf-Forschung (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
| | - Brigitte Pelzmann
- Division of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria; (S.S.); (K.Z.-P.)
| | - Ernst Malle
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria;
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Santos-Miranda A, Costa AD, Joviano-Santos JV, Rhana P, Bruno AS, Rocha P, Cau SB, Vieira LQ, Cruz JS, Roman-Campos D. Inhibition of calcium/calmodulin (Ca 2+ /CaM)-Calcium/calmodulin-dependent protein kinase II (CaMKII) axis reduces in vitro and ex vivo arrhythmias in experimental Chagas disease. FASEB J 2021; 35:e21901. [PMID: 34569665 DOI: 10.1096/fj.202101060r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 11/11/2022]
Abstract
Chagasic cardiomyopathy (CCC) is one of the main causes of heart failure and sudden death in Latin America. To date, there is no available medication to prevent or reverse the onset of cardiac symptoms. CCC occurs in a scenario of disrupted calcium dynamics and enhanced oxidative stress, which combined, may favor the hyper activation of calcium/calmodulin (Ca2+ /CaM)-calcium/calmodulin-dependent protein kinase II (CaMKII) (Ca2+ /CaM-CaMKII) pathway, which is fundamental for heart physiology and it is implicated in other cardiac diseases. Here, we evaluated the association between Ca2+ /CaM-CaMKII in the electro-mechanical (dys)function of the heart in the early stage of chronic experimental Trypanosoma cruzi infection. We observed that in vitro and ex vivo inhibition of Ca2+ /CaM-CaMKII reversed the arrhythmic profile of isolated hearts and isolated left-ventricles cardiomyocytes. The benefits of the limited Ca2+ /CaM-CaMKII activation to cardiomyocytes' electrical properties are partially related to the restoration of Ca2+ dynamics in a damaged cellular environment created after T. cruzi infection. Moreover, Ca2+ /CaM-CaMKII inhibition prevented the onset of arrhythmic contractions on isolated heart preparations of chagasic mice and restored the responsiveness to the increase in the left-ventricle pre-load. Taken together, our data provide the first experimental evidence for the potential of targeting Ca2+ /CaM-CaMKII pathway as a novel therapeutic target to treat CCC.
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Affiliation(s)
| | - Alexandre D Costa
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Paula Rhana
- Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Alexandre Santos Bruno
- Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Peter Rocha
- Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Stefany Bruno Cau
- Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Leda Q Vieira
- Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Jader S Cruz
- Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Danilo Roman-Campos
- Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil
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Gager GM, von Lewinski D, Sourij H, Jilma B, Eyileten C, Filipiak K, Hülsmann M, Kubica J, Postula M, Siller-Matula JM. Effects of SGLT2 Inhibitors on Ion Homeostasis and Oxidative Stress associated Mechanisms in Heart Failure. Biomed Pharmacother 2021; 143:112169. [PMID: 34560555 DOI: 10.1016/j.biopha.2021.112169] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/21/2022] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors present a class of antidiabetic drugs, which inhibit renal glucose reabsorption resulting in the elevation of urinary glucose levels. Within the past years, SGLT2 inhibitors have become increasingly relevant due to their effects beyond glycemic control in patients with type 2 diabetes (T2DM). Although dedicated large trials demonstrated cardioprotective effects of SGLT2 inhibitors, the exact mechanisms responsible for those benefits have not been fully identified. Alterations in Ca2+ signaling and oxidative stress accompanied by excessive reactive oxygen species (ROS) production, fibrosis and inflammatory processes form cornerstones of potential molecular targets for SGLT2 inhibitors. This review focused on three hypotheses for SGLT2 inhibitor-mediated cardioprotection: ion homeostasis, oxidative stress and endothelial dysfunction.
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Affiliation(s)
- Gloria M Gager
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Austria
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
| | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Austria
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Krzysztof Filipiak
- First Chair and Department of Cardiology, Medical University of Warsaw, Poland
| | - Martin Hülsmann
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria
| | - Jacek Kubica
- Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Jolanta M Siller-Matula
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria; Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland.
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32
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Chen JJ, Zhang LN, Wang HN, Xie CC, Li WY, Gao P, Hu WZ, Zhao ZF, Ji K. FAK inhibitor PF-431396 suppresses IgE-mediated mast cell activation and allergic inflammation in mice. Biochem Pharmacol 2021; 192:114722. [PMID: 34384759 DOI: 10.1016/j.bcp.2021.114722] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/25/2021] [Accepted: 08/02/2021] [Indexed: 12/14/2022]
Abstract
Mast cells (MCs) initiate and maintain allergic inflammation. Upon being stimulated with immunoglobulin (Ig)E and antigen (Ag), MCs exhibit FcεRI (high-affinity IgE) receptor-mediated degranulation, cytokine secretion, and increased focal adhesion kinase (FAK) activity. The aims of this study were to examine mechanisms of FAK regulation in IgE-mediated MC activation and the effects of FAK inhibition on MC-mediated allergic responses. FAK activity was manipulated with short hairpin RNA (shRNA) knockdown, FAK overexpression, and the FAK inhibitor PF-431396 (PF). Gene expression and kinase activation were analyzed with quantitative molecular biology assays. PF effects were tested in the passive cutaneous anaphylaxis (PCA), active systemic anaphylaxis (ASA), and allergic conjunctivitis (AC) mouse models. Our results showed that FAK overexpression increased IgE-mediated degranulation and reduced the dexamethasone inhibitory effect on MCs activation. The FAK inhibitor PF diminished MC release of β-hexosaminidase (β-hex), histamine, and inflammatory cytokines, via a mechanism that involves MAPK and NF-κB signaling pathways. CaMKII was identified as a robust FAK-associating protein. Inhibition of CaMKII activation by KN-93 suppressed FAK activity and its downstream pathway. PF attenuated inflammatory responses in our PCA and ASA models, and relieved signs of allergic disease in AC model mice. In conclusions, MC degranulation and production of inflammatory mediators in allergic disease may be consequent to FcεRI crosslinking inducing CaMKII-mediated activation of FAK activity. FAK inhibition may represent a new MC-suppressing treatment strategy for the treatment of allergic diseases.
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Affiliation(s)
- Jia-Jie Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Laboratory Department of South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518060, China.
| | - Li-Na Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Laboratory Department of South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Hui-Na Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Laboratory Department of South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Chu-Chu Xie
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Laboratory Department of South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Wei-Yong Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Laboratory Department of South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Pan Gao
- Shenzhen University General Hospital, Shenzhen 518060, China
| | - Wan-Zhen Hu
- Shenzhen University General Hospital, Shenzhen 518060, China
| | - Zhen-Fu Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Laboratory Department of South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Kunmei Ji
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Laboratory Department of South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518060, China.
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Zhang X, Connelly J, Levitan ES, Sun D, Wang JQ. Calcium/Calmodulin-Dependent Protein Kinase II in Cerebrovascular Diseases. Transl Stroke Res 2021; 12:513-529. [PMID: 33713030 PMCID: PMC8213567 DOI: 10.1007/s12975-021-00901-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/20/2020] [Accepted: 02/17/2021] [Indexed: 12/11/2022]
Abstract
Cerebrovascular disease is the most common life-threatening and debilitating condition that often leads to stroke. The multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key Ca2+ sensor and an important signaling protein in a variety of biological systems within the brain, heart, and vasculature. In the brain, past stroke-related studies have been mainly focused on the role of CaMKII in ischemic stroke in neurons and established CaMKII as a major mediator of neuronal cell death induced by glutamate excitotoxicity and oxidative stress following ischemic stroke. However, with growing understanding of the importance of neurovascular interactions in cerebrovascular diseases, there are clearly gaps in our understanding of how CaMKII functions in the complex neurovascular biological processes and its contributions to cerebrovascular diseases. Additionally, emerging evidence demonstrates novel regulatory mechanisms of CaMKII and potential roles of the less-studied CaMKII isoforms in the ischemic brain, which has sparked renewed interests in this dynamic kinase family. This review discusses past findings and emerging evidence on CaMKII in several major cerebrovascular dysfunctions including ischemic stroke, hemorrhagic stroke, and vascular dementia, focusing on the unique roles played by CaMKII in the underlying biological processes of neuronal cell death, neuroinflammation, and endothelial barrier dysfunction triggered by stroke. We also highlight exciting new findings, promising therapeutic agents, and future perspectives for CaMKII in cerebrovascular systems.
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Affiliation(s)
- Xuejing Zhang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, E1354 BST, Pittsburgh, PA, USA
| | - Jaclyn Connelly
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, E1354 BST, Pittsburgh, PA, USA
| | - Edwin S Levitan
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, E1354 BST, Pittsburgh, PA, USA
| | - Dandan Sun
- Department of Neurology, Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, 7016 Biomedical Science Tower-3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA.
| | - Jane Q Wang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, E1354 BST, Pittsburgh, PA, USA.
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Racioppi MF, Burgos JI, Morell M, Gonano LA, Vila Petroff M. Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime. J Am Heart Assoc 2021; 10:e018833. [PMID: 34219467 PMCID: PMC8483492 DOI: 10.1161/jaha.120.018833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Istaroxime is an inhibitor of Na+/K+ ATPase with proven efficacy to increase cardiac contractility and to accelerate relaxation attributable to a relief in phospholamban‐dependent inhibition of the sarcoplasmic reticulum Ca2+ ATPase. We have previously shown that pharmacologic Na+/K+ ATPase inhibition promotes calcium/calmodulin‐dependent kinase II activation, which mediates both cardiomyocyte death and arrhythmias. Here, we aim to compare the cardiotoxic effects promoted by classic pharmacologic Na+/K+ ATPase inhibition versus istaroxime. Methods and Results Ventricular cardiomyocytes were treated with ouabain or istaroxime at previously tested equi‐inotropic concentrations to compare their impact on cell viability, apoptosis, and calcium/calmodulin‐dependent kinase II activation. In contrast to ouabain, istaroxime neither promoted calcium/calmodulin‐dependent kinase II activation nor cardiomyocyte death. In addition, we explored the differential behavior promoted by ouabain and istaroxime on spontaneous diastolic Ca2+ release. In rat cardiomyocytes, istaroxime did not significantly increase Ca2+ spark and wave frequency but increased the proportion of aborted Ca2+ waves. Further insight was provided by studying cardiomyocytes from mice that do not express phospholamban. In this model, the lower Ca2+ wave incidence observed with istaroxime remains present, suggesting that istaroxime‐dependent relief on phospholamban‐dependent sarcoplasmic reticulum Ca2+ ATPase 2A inhibition is not the unique mechanism underlying the low arrhythmogenic profile of this drug. Conclusions Our results indicate that, different from ouabain, istaroxime can reach a significant inotropic effect without leading to calcium/calmodulin‐dependent kinase II–dependent cardiomyocyte death. Additionally, we provide novel insights regarding the low arrhythmogenic impact of istaroxime on cardiac Ca2+ handling.
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Affiliation(s)
- María Florencia Racioppi
- Centro de Investigaciones Cardiovasculares Horacio Cingolani CONICET La Plata Facultad de Ciencias Médicas Universidad Nacional de La Plata Argentina
| | - Juan Ignacio Burgos
- Centro de Investigaciones Cardiovasculares Horacio Cingolani CONICET La Plata Facultad de Ciencias Médicas Universidad Nacional de La Plata Argentina
| | - Malena Morell
- Centro de Investigaciones Cardiovasculares Horacio Cingolani CONICET La Plata Facultad de Ciencias Médicas Universidad Nacional de La Plata Argentina
| | - Luis Alberto Gonano
- Centro de Investigaciones Cardiovasculares Horacio Cingolani CONICET La Plata Facultad de Ciencias Médicas Universidad Nacional de La Plata Argentina
| | - Martín Vila Petroff
- Centro de Investigaciones Cardiovasculares Horacio Cingolani CONICET La Plata Facultad de Ciencias Médicas Universidad Nacional de La Plata Argentina
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Pleiotropic and Potentially Beneficial Effects of Reactive Oxygen Species on the Intracellular Signaling Pathways in Endothelial Cells. Antioxidants (Basel) 2021; 10:antiox10060904. [PMID: 34205032 PMCID: PMC8229098 DOI: 10.3390/antiox10060904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/28/2021] [Accepted: 05/31/2021] [Indexed: 02/06/2023] Open
Abstract
Endothelial cells (ECs) are exposed to molecular dioxygen and its derivative reactive oxygen species (ROS). ROS are now well established as important signaling messengers. Excessive production of ROS, however, results in oxidative stress, a significant contributor to the development of numerous diseases. Here, we analyze the experimental data and theoretical concepts concerning positive pro-survival effects of ROS on signaling pathways in endothelial cells (ECs). Our analysis of the available experimental data suggests possible positive roles of ROS in induction of pro-survival pathways, downstream of the Gi-protein-coupled receptors, which mimics insulin signaling and prevention or improvement of the endothelial dysfunction. It is, however, doubtful, whether ROS can contribute to the stabilization of the endothelial barrier.
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Liu Y, Shao Q, Cheng HJ, Li T, Zhang X, Callahan MF, Herrington D, Kitzman D, Zhao D, Cheng CP. Chronic Ca 2+/Calmodulin-Dependent Protein Kinase II Inhibition Rescues Advanced Heart Failure. J Pharmacol Exp Ther 2021; 377:316-325. [PMID: 33722881 PMCID: PMC8140392 DOI: 10.1124/jpet.120.000361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/11/2021] [Indexed: 11/22/2022] Open
Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is upregulated in congestive heart failure (CHF), contributing to electrical, structural, and functional remodeling. CaMKII inhibition is known to improve CHF, but its direct cardiac effects in CHF remain unclear. We hypothesized that CaMKII inhibition improves cardiomyocyte function, [Ca2+]i regulation, and β-adrenergic reserve, thus improving advanced CHF. In a 16-week study, we compared plasma neurohormonal levels and left ventricular (LV)- and myocyte-functional and calcium transient ([Ca2+]iT) responses in male Sprague-Dawley rats (10/group) with CHF induced by isoproterenol (170 mg/kg sq for 2 days). In rats with CHF, we studied the effects of the CaMKII inhibitor KN-93 or its inactive analog KN-92 (n = 4) (70 µg/kg per day, mini-pump) for 4 weeks. Compared with controls, isoproterenol-treated rats had severe CHF with 5-fold-increased plasma norepinephrine and about 50% decreases in ejection fraction (EF) and LV contractility [slope of LV end-systolic pressure-LV end-systolic volume relation (EES)] but increased time constant of LV relaxation (τ). They also showed significantly reduced myocyte contraction [maximum rate of myocyte shortening (dL/dtmax)], relaxation (dL/dtmax), and [Ca2+]iT Isoproterenol superfusion caused significantly fewer increases in dL/dtmax and [Ca2+]iT KN-93 treatment prevented plasma norepinephrine elevation, with increased basal and acute isoproterenol-stimulated increases in EF and EES and decreased τ in CHF. KN-93 treatment preserved normal myocyte contraction, relaxation, [Ca2+]iT, and β-adrenergic reserve, whereas KN-92 treatment failed to improve LV and myocyte function, and plasma norepinephrine remained high in CHF. Thus, chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system, restoring normal LV and cardiomyocyte basal and β-adrenergic-stimulated contraction, relaxation, and [Ca2+]iT, thereby playing a rescue role in advanced CHF. SIGNIFICANCE STATEMENT: We investigated the therapeutic efficacy of late initiation of chronic Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition on progression of advanced congestive heart failure (CHF). Chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system and restored normal intrinsic cardiomyocyte basal and β-adrenergic receptor-stimulated relaxation, contraction, and [Ca2+]i regulation, leading to reversal of CHF progression. These data provide new evidence that CaMKII inhibition is able and sufficient to rescue a failing heart, and thus cardiac CaMKII inhibition is a promising target for improving CHF treatment.
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Affiliation(s)
- Yixi Liu
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - Qun Shao
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - Heng-Jie Cheng
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - Tiankai Li
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - Xiaowei Zhang
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - Michael F Callahan
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - David Herrington
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - Dalane Kitzman
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - David Zhao
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
| | - Che-Ping Cheng
- Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)
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Yang Y, Jiang K, Liu X, Qin M, Xiang Y. CaMKII in Regulation of Cell Death During Myocardial Reperfusion Injury. Front Mol Biosci 2021; 8:668129. [PMID: 34141722 PMCID: PMC8204011 DOI: 10.3389/fmolb.2021.668129] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular disease is the leading cause of death worldwide. In spite of the mature managements of myocardial infarction (MI), post-MI reperfusion (I/R) injury results in high morbidity and mortality. Cardiomyocyte Ca2+ overload is a major factor of I/R injury, initiating a cascade of events contributing to cardiomyocyte death and myocardial dysfunction. Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in cardiomyocyte death response to I/R injury, whose activation is a key feature of myocardial I/R in causing intracellular mitochondrial swelling, endoplasmic reticulum (ER) Ca2+ leakage, abnormal myofilament contraction, and other adverse reactions. CaMKII is a multifunctional serine/threonine protein kinase, and CaMKIIδ, the dominant subtype in heart, has been widely studied in the activation, location, and related pathways of cardiomyocytes death, which has been considered as a potential targets for pharmacological inhibition. In this review, we summarize a brief overview of CaMKII with various posttranslational modifications and its properties in myocardial I/R injury. We focus on the molecular mechanism of CaMKII involved in regulation of cell death induced by myocardial I/R including necroptosis and pyroptosis of cardiomyocyte. Finally, we highlight that targeting CaMKII modifications and cell death involved pathways may provide new insights to understand the conversion of cardiomyocyte fate in the setting of myocardial I/R injury.
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Affiliation(s)
- Yingjie Yang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Kai Jiang
- Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xu Liu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Mu Qin
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yaozu Xiang
- Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
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Liu X, Wang S, Guo X, Li Y, Ogurlu R, Lu F, Prondzynski M, Buzon SDLS, Ma Q, Zhang D, Wang G, Cotton J, Guo Y, Xiao L, Milan DJ, Xu Y, Schlame M, Bezzerides VJ, Pu WT. Increased Reactive Oxygen Species-Mediated Ca 2+/Calmodulin-Dependent Protein Kinase II Activation Contributes to Calcium Handling Abnormalities and Impaired Contraction in Barth Syndrome. Circulation 2021; 143:1894-1911. [PMID: 33793303 PMCID: PMC8691127 DOI: 10.1161/circulationaha.120.048698] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Mutations in tafazzin (TAZ), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood. METHODS We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac-specific TAZ knockout mice. Using cardiomyocytes derived from human induced pluripotent stem cells and cardiac-specific TAZ knockout mice as model systems, we investigated the effect of TAZ inactivation on Ca2+ handling. Through genome editing and pharmacology, we defined a molecular link between TAZ mutation and abnormal Ca2+ handling and contractility. RESULTS A subset of mice with cardiac-specific TAZ inactivation developed arrhythmias, including bidirectional ventricular tachycardia, atrial tachycardia, and complete atrioventricular block. Compared with wild-type controls, BTHS-induced pluripotent stem cell-derived cardiomyocytes had increased diastolic Ca2+ and decreased Ca2+ transient amplitude. BTHS-induced pluripotent stem cell-derived cardiomyocytes had higher levels of mitochondrial and cellular reactive oxygen species than wild-type controls, which activated CaMKII (Ca2+/calmodulin-dependent protein kinase II). Activated CaMKII phosphorylated the RYR2 (ryanodine receptor 2) on serine 2814, increasing Ca2+ leak through RYR2. Inhibition of this reactive oxygen species-CaMKII-RYR2 pathway through pharmacological inhibitors or genome editing normalized aberrant Ca2+ handling in BTHS-induced pluripotent stem cell-derived cardiomyocytes and improved their contractile function. Murine Taz knockout cardiomyocytes also exhibited elevated diastolic Ca2+ and decreased Ca2+ transient amplitude. These abnormalities were ameliorated by Ca2+/calmodulin-dependent protein kinase II or reactive oxygen species inhibition. CONCLUSIONS This study identified a molecular pathway that links TAZ mutation with abnormal Ca2+ handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat BTHS and potentially other diseases with elevated mitochondrial reactive oxygen species production.
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Affiliation(s)
- Xujie Liu
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Radiology, Basic Medical School, Chongqing Medical University, Chongqing, 400016, China
| | - Suya Wang
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Xiaoling Guo
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
- Center of Scientific Research, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Yifei Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Roza Ogurlu
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Fujian Lu
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
| | | | | | - Qing Ma
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Donghui Zhang
- State key laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, Hubei 430062, China
| | - Gang Wang
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Justin Cotton
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
- Harvard College, Cambridge, MA 02138, USA
| | - Yuxuan Guo
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Ling Xiao
- Department of Cardiology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - David J. Milan
- Department of Cardiology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Yang Xu
- Department of Anesthesiology, New York University School of Medicine, New York, New York
| | - Michael Schlame
- Department of Anesthesiology, New York University School of Medicine, New York, New York
| | | | - William T. Pu
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
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Wang L, Ginnan RG, Wang YX, Zheng YM. Interactive Roles of CaMKII/Ryanodine Receptor Signaling and Inflammation in Lung Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:305-317. [PMID: 33788199 DOI: 10.1007/978-3-030-63046-1_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional protein kinase and has been recently recognized to play a vital role in pathological events in the pulmonary system. CaMKII has diverse downstream targets that promote vascular disease, asthma, and cancer, so improved understanding of CaMKII signaling has the potential to lead to new therapies for lung diseases. Multiple studies have demonstrated that CaMKII is involved in redox modulation of ryanodine receptors (RyRs). CaMKII can be directly activated by reactive oxygen species (ROS) which then regulates RyR activity, which is essential for Ca2+-dependent processes in lung diseases. Furthermore, both CaMKII and RyRs participate in the inflammation process. However, their role in the pulmonary physiology in response to ROS is still an ambiguous one. Because CaMKII and RyRs are important in pulmonary biology, cell survival, cell cycle control, and inflammation, it is possible that the relationship between ROS and CaMKII/RyRs signal complex will be necessary for understanding and treating lung diseases. Here, we review roles of CaMKII/RyRs in lung diseases to understand with how CaMKII/RyRs may act as a transduction signal to connect prooxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of pulmonary disease.
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Affiliation(s)
- Lan Wang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.,Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Roman G Ginnan
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Yong-Xiao Wang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
| | - Yun-Min Zheng
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
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Bouviere J, Fortunato RS, Dupuy C, Werneck-de-Castro JP, Carvalho DP, Louzada RA. Exercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle. Antioxidants (Basel) 2021; 10:antiox10040537. [PMID: 33808211 PMCID: PMC8066165 DOI: 10.3390/antiox10040537] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/16/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022] Open
Abstract
Physical exercise represents a major challenge to whole-body homeostasis, provoking acute and adaptative responses at the cellular and systemic levels. Different sources of reactive oxygen species (ROS) have been described in skeletal muscle (e.g., NADPH oxidases, xanthine oxidase, and mitochondria) and are closely related to the physiological changes induced by physical exercise through the modulation of several signaling pathways. Many signaling pathways that are regulated by exercise-induced ROS generation, such as adenosine monophosphate-activated protein kinase (AMPK), mitogen activated protein kinase (MAPK), nuclear respiratory factor2 (NRF2), and PGC-1α are involved in skeletal muscle responses to physical exercise, such as increased glucose uptake, mitochondriogenesis, and hypertrophy, among others. Most of these adaptations are blunted by antioxidants, revealing the crucial role played by ROS during and after physical exercise. When ROS generation is either insufficient or exacerbated, ROS-mediated signaling is disrupted, as well as physical exercise adaptations. Thus, an understanding the limit between "ROS that can promote beneficial effects" and "ROS that can promote harmful effects" is a challenging question in exercise biology. The identification of new mediators that cause reductive stress and thereby disrupt exercise-stimulated ROS signaling is a trending on this topic and are covered in this current review.
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Affiliation(s)
- Jessica Bouviere
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Rodrigo S. Fortunato
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Corinne Dupuy
- Université Paris-Saclay, UMR 9019CNRS, Gustave Roussy, 94800 Villejuif, France;
| | - Joao Pedro Werneck-de-Castro
- Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Denise P. Carvalho
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Ruy A. Louzada
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
- Université Paris-Saclay, UMR 9019CNRS, Gustave Roussy, 94800 Villejuif, France;
- Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- Correspondence:
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Gbr AA, Abdel Baky NA, Mohamed EA, Zaky HS. Cardioprotective effect of pioglitazone and curcumin against diabetic cardiomyopathy in type 1 diabetes mellitus: impact on CaMKII/NF-κB/TGF-β1 and PPAR-γ signaling pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:349-360. [PMID: 32984914 DOI: 10.1007/s00210-020-01979-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/16/2020] [Indexed: 12/14/2022]
Abstract
Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients, which is currently without available specific treatment. This study aimed to investigate the potential protective effects of pioglitazone (Pio) and curcumin (Cur) against DCM in type 1 diabetes mellitus (T1DM), with pointing to their role on Ca+2/calmodulin-dependent protein kinase II (CaMKII) and peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. Diabetes was induced in adult male Sprague Dawley rats by administration of single intraperitoneal injection of streptozotocin (STZ) (52.5 mg/kg). Diabetic rats were administered either Pio (20 mg/kg/day) or Cur (100 mg/kg/day) orally for 6 weeks. Treatment with Pio and/or Cur markedly reduced serum cardiac injury markers and lipid profile markers in diabetic animals. Additionally, Pio and/or Cur treatment mitigated oxidative stress and fibrosis in diabetic rats as evident from the significant suppression in myocardial lipid peroxidation and tumor growth factor beta 1 (TGF-β1) level, with concomitant significant elevation in total antioxidant capacity (TAC) and improvement in histopathological architecture of heart tissue. Pio/Cur treatment protocol accomplished its cardioprotective effect by depressing cardiac CaMKII/NF-κB signaling accompanied by enhancement in PPAR-γ expression. Conclusively, these findings demonstrated the therapeutic potential of Pio/Cur regimen in alleviating DCM in T1DM through modulation of CaMKII and PPAR-γ expression. Graphical Abstract.
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Affiliation(s)
- Aya A Gbr
- Egypt Ministry of Health and Population, Cairo, Egypt
| | - Nayira A Abdel Baky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Naser City, Cairo, P.N.11754, Egypt.
| | - Eman A Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Naser City, Cairo, P.N.11754, Egypt
| | - Heba S Zaky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Naser City, Cairo, P.N.11754, Egypt
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Brown SM, Larsen NK, Thankam FG, Agrawal DK. Fetal cardiomyocyte phenotype, ketone body metabolism, and mitochondrial dysfunction in the pathology of atrial fibrillation. Mol Cell Biochem 2020; 476:1165-1178. [PMID: 33188453 DOI: 10.1007/s11010-020-03980-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/06/2020] [Indexed: 10/23/2022]
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Even though hypertension, congestive heart failure, pulmonary disease, and coronary artery disease are the potential risk factors for AF, the underlying molecular pathology is largely unknown. The reversion of the mature cardiomyocytes to fetal phenotype, impaired ketone body metabolism, mitochondrial dysfunction, and the cellular effect of reactive oxygen species (ROS) are the major underlying biochemical events associated with the molecular pathology of AF. On this background, the present manuscript sheds light into these biochemical events in regard to the metabolic derangements in cardiomyocyte leading to AF, especially with respect to structural, contractile, and electrophysiological properties. In addition, the article critically reviews the current understanding, potential demerits, and translational strategies in the management of AF.
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Affiliation(s)
- Sean M Brown
- Creighton University School of Medicine, Omaha, NE, 68178, USA
| | | | - Finosh G Thankam
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766, USA.
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Roselló-Díez E, Hove-Madsen L, Pérez-Grijalba V, Muñoz-Guijosa C, Artigas V, Maria Padró J, Domínguez-Garrido E. Mitochondrial genetic effect on atrial fibrillation: A case-control study. Mitochondrion 2020; 56:15-24. [PMID: 33171269 DOI: 10.1016/j.mito.2020.11.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/25/2020] [Accepted: 11/04/2020] [Indexed: 12/11/2022]
Abstract
Atrial fibrillation (AF) is a common arrhythmia in the general population and following cardiac surgery. The influence of mitochondrial genomics on AF pathogenesis is not fully understood. We analyzed mitochondrial variables from 78 human atrial samples collected from cardiac surgeries in the following groups: 1) permanent preoperative AF; 2) preoperative sinus rhythm (SR) with postoperative AF; and 3) pre-/postoperative SR. Haplogroup H appeared offer protection against, and haplogroup U predispose to permanent AF. mtDNA content was higher in group 2 than in 3. These findings contribute to a better understanding of the influence of mitochondria on AF pathogenesis.
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Affiliation(s)
- Elena Roselló-Díez
- Department of Cardiac Surgery, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, 167 Sant Antoni Maria Claret Street, 08025 Barcelona, Spain.
| | - Leif Hove-Madsen
- Cardiovascular Research Centre (CSIC) and CIBERCV, 167 Sant Antoni Maria Claret Street, 08025 Barcelona, Spain
| | - Virginia Pérez-Grijalba
- Molecular Diagnostic Unit, Fundación Rioja Salud (FRS), 98 Piqueras Street, 26006 Logroño, Spain
| | - Christian Muñoz-Guijosa
- Department of Cardiac Surgery, Universitat Autònoma de Barcelona, Hospital Universitario Germans Trias i Pujol, Canyet Road, 08916 Badalona, Spain
| | - Vicenç Artigas
- Department of General and Digestive Surgery, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, 167 Sant Antoni Maria Claret Street, 08025 Barcelona, Spain
| | - Josep Maria Padró
- Department of Cardiac Surgery, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, 167 Sant Antoni Maria Claret Street, 08025 Barcelona, Spain
| | - Elena Domínguez-Garrido
- Molecular Diagnostic Unit, Fundación Rioja Salud (FRS), 98 Piqueras Street, 26006 Logroño, Spain
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Barnes A, Campbell C, Weiss R, Kahwash R. Cardiac Contractility Modulation in Heart Failure: Mechanisms and Clinical Evidence. CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE 2020. [DOI: 10.1007/s11936-020-00852-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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45
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Beghi S, Cavaliere F, Buschini A. Gene polymorphisms in calcium-calmodulin pathway: Focus on cardiovascular disease. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2020; 786:108325. [PMID: 33339582 DOI: 10.1016/j.mrrev.2020.108325] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 07/22/2020] [Accepted: 07/24/2020] [Indexed: 12/30/2022]
Abstract
Cardiovascular disease is the leading cause of death in industrialized countries and affects an increasing number of people. Several risk factors play an important role in the etiology of this disease, such as an unhealthy lifestyle. It is increasingly clear that genetic factors influencing the molecular basis of excitation-contraction mechanisms in the heart could contribute to modify the individual's risk. Thanks to the progress that has been made in understanding calcium signaling in the heart, it is assumed that calmodulin can play a crucial role in the excitation-contraction coupling. In fact, calmodulin (CaM) binds calcium and consequently regulates calcium channels. Several works show how some polymorphic variants can be considered predisposing factors to complex pathologies. Therefore, we hypothesize that the identification of polymorphic variants of proteins involved in the CaM pathway could be important for understanding how genetic traits can influence predisposition to myocardial infarction. This review considers each pathway of the three different isoforms of calmodulin (CaM1; CaM2; CaM3) and focuses on some common proteins involved in the three pathways, with the aim of analyzing the polymorphisms studied in the literature and understanding if they are associated with cardiovascular disease.
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Affiliation(s)
- Sofia Beghi
- University of Parma, Department of Chemistry, Life Sciences and Environmental Sustainability, Parco Area Delle Scienze 11A, 43124, Parma, Italy
| | - Francesca Cavaliere
- University of Parma, Department of Food and Drug, Parco Area Delle Scienze 17A, 43124, Parma, Italy
| | - Annamaria Buschini
- University of Parma, Department of Chemistry, Life Sciences and Environmental Sustainability, Parco Area Delle Scienze 11A, 43124, Parma, Italy.
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Role of Oxidation-Dependent CaMKII Activation in the Genesis of Abnormal Action Potentials in Atrial Cardiomyocytes: A Simulation Study. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1597012. [PMID: 32685443 PMCID: PMC7327560 DOI: 10.1155/2020/1597012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 05/20/2020] [Accepted: 06/02/2020] [Indexed: 01/04/2023]
Abstract
Atrial fibrillation is a common cardiac arrhythmia with an increasing incidence rate. Particularly for the aging population, understanding the underlying mechanisms of atrial arrhythmia is important in designing clinical treatment. Recently, experiments have shown that atrial arrhythmia is associated with oxidative stress. In this study, an atrial cell model including oxidative-dependent Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII) activation was developed to explore the intrinsic mechanisms of atrial arrhythmia induced by oxidative stress. The simulation results showed that oxidative stress caused early afterdepolarizations (EADs) of action potentials by altering the dynamics of transmembrane currents and intracellular calcium cycling. Oxidative stress gradually elevated the concentration of calcium ions in the cytoplasm by enhancing the L-type Ca2+ current and sarcoplasmic reticulum (SR) calcium release. Owing to increased intracellular calcium concentration, the inward Na+/Ca2+ exchange current was elevated which slowed down the repolarization of the action potential. Thus, the action potential was prolonged and the L-type Ca2+ current was reactivated, resulting in the genesis of EAD. Furthermore, based on the atrial single-cell model, a two-dimensional (2D) ideal tissue model was developed to explore the effect of oxidative stress on the electrical excitation wave conduction in 2D tissue. Simulation results demonstrated that, under oxidative stress conditions, EAD hindered the conduction of electrical excitation and caused an unstable spiral wave, which could disrupt normal cardiac rhythm and cause atrial arrhythmia. This study showed the effects of excess reactive oxygen species on calcium cycling and action potential in atrial myocytes and provided insights regarding atrial arrhythmia induced by oxidative stress.
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Macedo FN, Souza DSD, Araújo JEDS, Dantas CO, Miguel-Dos-Santos R, Silva-Filha E, Rabelo TK, Dos Santos RV, Zhang R, Barreto AS, Vasconcelos CMLD, Lauton-Santos S, Santos MRVD, Quintans-Júnior LJ, Santana-Filho VJ, Mesquita TRR. NOX-dependent reactive oxygen species production underlies arrhythmias susceptibility in dexamethasone-treated rats. Free Radic Biol Med 2020; 152:1-7. [PMID: 32147395 DOI: 10.1016/j.freeradbiomed.2020.03.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 03/04/2020] [Indexed: 12/17/2022]
Abstract
Dexamethasone is the most clinically used glucocorticoid with an established role in the treatment of a wide spectrum of inflammatory-related diseases. While the therapeutic actions are well known, dexamethasone treatment causes a number of cardiovascular side effects, which are complex, frequent and, in some cases, clinically unnoticeable. Here, we investigated whether a therapeutic regimen of dexamethasone affects cardiac arrhythmogenesis, focusing on the contribution of Nox-derived reactive oxygen species (ROS). Male Wistar rats were treated with dexamethasone (2 mg/kg, i.p.) for 7 days. Afterward, hemodynamic measurements, autonomic modulation, left ventricular function, cardiac fibrosis, reactive oxygen species (ROS) generation, Nox protein expression, superoxide dismutase (SOD) and catalase activities, and arrhythmias incidence were evaluated. Here, we show that dexamethasone increases blood pressure, associated with enhanced cardiac and vascular sympathetic modulation. Moreover, a marked increase in the cardiac ROS generation was observed, whereas the enhanced SOD activity did not prevent the higher levels of lipid peroxidation in the dexamethasone group. On the other hand, increased cardiac Nox 4 expression and hydrogen peroxide decomposition rate was observed in dexamethasone-treated rats, while Nox 2 remained unchanged. Interestingly, although preserved ventricular contractility and β-adrenergic responsiveness, we found that dexamethasone-treated rats displayed greater interstitial and perivascular fibrosis than control. Surprisingly, despite the absence of arrhythmias at basal condition, we demonstrated, by in vivo and ex vivo approaches, that dexamethasone-treated rats are more susceptible to develop harmful forms of ventricular arrhythmias when challenged with pharmacological drugs or burst pacing-induced arrhythmias. Notably, concomitant treatment with apocynin, an inhibitor of NADPH oxidase, prevented these ectopic ventricular events. Together, our results reveal that hearts become arrhythmogenic during dexamethasone treatment, uncovering the pivotal role of ROS-generating NADPH oxidases for arrhythmias vulnerability.
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Affiliation(s)
- Fabricio Nunes Macedo
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil; Estácio University of Sergipe, Aracaju, Brazil
| | | | | | | | - Rodrigo Miguel-Dos-Santos
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil; Department of Circulation and Medical Imaging, St. Olav's Hospital, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | | | | | - Robervan Vidal Dos Santos
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil; Estácio University of Sergipe, Aracaju, Brazil
| | - Rui Zhang
- Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, United States; Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - André Sales Barreto
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil; Department of Health Education, Federal University of Sergipe, Lagarto, Brazil
| | | | | | | | | | | | - Thássio Ricardo Ribeiro Mesquita
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil; Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, United States.
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Himelman E, Lillo MA, Nouet J, Gonzalez JP, Zhao Q, Xie LH, Li H, Liu T, Wehrens XH, Lampe PD, Fishman GI, Shirokova N, Contreras JE, Fraidenraich D. Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy. J Clin Invest 2020; 130:1713-1727. [PMID: 31910160 PMCID: PMC7108916 DOI: 10.1172/jci128190] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 12/18/2019] [Indexed: 12/11/2022] Open
Abstract
Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized that hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knockin mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or nonphosphorylatable alanines (mdxS3A). The mdxS3E, but not mdxS3A, mice were resistant to Cx43 remodeling, with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca2+ signaling and a reduction of NADPH oxidase 2 (NOX2)/ROS production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality, and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation, and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43 remodeling and suggest that targeting Cx43 may be a therapeutic strategy for preventing heart dysfunction and arrhythmias in DMD patients.
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Affiliation(s)
| | | | - Julie Nouet
- Department of Cell Biology and Molecular Medicine
| | | | - Qingshi Zhao
- Department of Cell Biology and Molecular Medicine
| | - Lai-Hua Xie
- Department of Cell Biology and Molecular Medicine
| | - Hong Li
- Center for Advanced Proteomics Research, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA
| | - Tong Liu
- Center for Advanced Proteomics Research, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA
| | - Xander H.T. Wehrens
- Department of Molecular Physiology and Biophysics, Medicine, Neuroscience, and Pediatrics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas, USA
| | - Paul D. Lampe
- Fred Hutchinson Cancer Research Center, Translational Research Program, Public Health Sciences Division, Seattle, Washington, USA
| | - Glenn I. Fishman
- Leon H. Charney Division of Cardiology, New York University Langone Health, New York, New York, USA
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Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3690123. [PMID: 32064022 PMCID: PMC6998749 DOI: 10.1155/2020/3690123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 11/01/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Abstract
Thioridazine (THIO) is a phenothiazine derivative that is mainly used for the treatment of psychotic disorders. However, cardiac arrhythmias especially QT interval prolongation associated with the application of this compound have received serious attention after its introduction into clinical practice, and the mechanisms underlying the cardiotoxicity induced by THIO have not been well defined. The present study was aimed at exploring the long-term effects of THIO on the hERG and L-type calcium channels, both of which are relevant to the development of QT prolongation. The hERG current (I hERG) and the calcium current (I Ca-L) were measured by patch clamp techniques. Protein levels were analyzed by Western blot, and channel-chaperone interactions were determined by coimmunoprecipitation. Reactive oxygen species (ROS) were determined by flow cytometry and laser scanning confocal microscopy. Our results demonstrated that THIO induced hERG channel deficiency but did not alter channel kinetics. THIO promoted ROS production and stimulated endoplasmic reticulum (ER) stress and the related proteins. The ROS scavenger N-acetyl cysteine (NAC) significantly attenuated hERG reduction induced by THIO and abolished the upregulation of ER stress marker proteins. Meanwhile, THIO increased the degradation of hERG channels via disrupting hERG-Hsp70 interactions. The disordered hERG proteins were degraded in proteasomes after ubiquitin modification. On the other hand, THIO increased I Ca-L density and intracellular Ca2+ ([Ca2+]i) in neonatal rat ventricular cardiomyocytes (NRVMs). The specific CaMKII inhibitor KN-93 attenuated the intracellular Ca2+ overload, indicating that ROS-mediated CaMKII activation promoted calcium channel activation induced by THIO. Optical mapping analysis demonstrated the slowing effects of THIO on cardiac repolarization in mouse hearts. THIO significantly prolonged APD50 and APD90 and increased the incidence of early afterdepolarizations (EADs). In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), THIO also resulted in APD prolongation. In conclusion, dysfunction of hERG channel proteins and activation of L-type calcium channels via ROS production might be the ionic mechanisms for QT prolongation induced by THIO.
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50
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Yang X, An N, Zhong C, Guan M, Jiang Y, Li X, Zhang H, Wang L, Ruan Y, Gao Y, Liu N, Shang H, Xing Y. Enhanced cardiomyocyte reactive oxygen species signaling promotes ibrutinib-induced atrial fibrillation. Redox Biol 2020; 30:101432. [PMID: 31986467 PMCID: PMC6994714 DOI: 10.1016/j.redox.2020.101432] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/27/2019] [Accepted: 01/12/2020] [Indexed: 12/12/2022] Open
Abstract
Atrial fibrillation (AF) occurs in up to 11% of cancer patients treated with ibrutinib. The pathophysiology of ibrutinib promoted AF is complicated, as there are multiple interactions involved; the detailed molecular mechanisms underlying this are still unclear. Here, we aimed to determine the electrophysiological and molecular mechanisms of burst-pacing-induced AF in ibrutinib-treated mice. The results indicated differentially expressed proteins in ibrutinib-treated mice, identified through proteomic analysis, were found to play a role in oxidative stress-related pathways. Finally, treatment with an inhibitor of NADPH oxidase (NOX) prevented and reversed AF development in ibrutinib-treated mice. It was showed that the related protein expression of reactive oxygen species (ROS) in the ibrutinib group was significantly increased, including NOX2, NOX4, p22-phox, XO and TGF-β protein expression. It was interesting that ibrutinib group also significantly increased the expression of ox-CaMKII, p-CaMKII (Thr-286) and p-RyR2 (Ser2814), causing enhanced abnormal sarcoplasmic reticulum (SR) Ca2+ release and mitochondrial structures, as well as atrial fibrosis and atrial hypertrophy in ibrutinib-treated mice, and apocynin reduced the expression of these proteins. Ibrutinib-treated mice were also more likely to develop AF, and AF occurred over longer periods. In conclusion, our study has established a pathophysiological role for ROS signaling in atrial cardiomyocytes, and it may be that ox-CaMKII and p-CaMKII (Thr-286) are activated by ROS to increase AF susceptibility following ibrutinib treatment. We have also identified the inhibition of NOX as a potential novel AF therapy approach.
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Affiliation(s)
- Xinyu Yang
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China; Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Na An
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China; Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Changming Zhong
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Manke Guan
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yuchen Jiang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xinye Li
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Hanlai Zhang
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Liqin Wang
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yanfei Ruan
- Department of Cardiology, Beijing An Zhen Hospital of the Capital University of Medical Sciences, Beijing, 100853, PR China
| | - Yonghong Gao
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Nian Liu
- Department of Cardiology, Beijing An Zhen Hospital of the Capital University of Medical Sciences, Beijing, 100853, PR China.
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Yanwei Xing
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
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