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Katnahji N, Matthes J. Opposite effects of Gα i2 or Gα i3 deficiency on reduced basal density and attenuated β-adrenergic response of ventricular Ca 2+ currents in myocytes of mice overexpressing the cardiac β 1-adrenoceptor. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03999-y. [PMID: 40163150 DOI: 10.1007/s00210-025-03999-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 02/27/2025] [Indexed: 04/02/2025]
Abstract
Ca2+ currents (ICaL) carried by ventricular L-type Ca2+ channels (LTCC) are altered in failing hearts, and increased LTCC activity is discussed as a cause of cardiomyopathy. We have shown that lack of the inhibitory G-protein isoform Gαi3 improves cardiac outcome and survival in a murine heart-failure model of cardiac β1-adrenoceptor (β1-AR) overexpression (β1-tg), while lack of the Gαi2 isoform was detrimental in the same heart-failure model. Given the potential role of LTCC and their modulation by β-adrenergic signalling, we now analysed ventricular ICaL in β1-tg mice and in β1-tg mice lacking either Gαi2 or Gαi3. Using the patch-clamp technique, we recorded whole-cell ICaL in ventricular myocytes freshly isolated from adult mice. Compared to age-matched wild-type littermates, basal ICaL was reduced in myocytes from β1-tg mice both under basal conditions (- 8.1 ± 1.6 vs. - 5.5 ± 1.5 pA/pF) and upon β-adrenergic stimulation with 1 µM isoproterenol (- 14.3 ± 5.6 vs. - 7.4 ± 1.9 pA/pF). Lack of Gαi3 normalised basal ICaL to nearly wild-type levels (- 7.5 ± 1.6 pA/pF), while β-adrenergic response remained attenuated (- 9.5 ± 3.6 pA/pF). In contrast, the absence of Gαi2 did not restore basal ICaL (- 5.7 ± 1.8 pA/pF), but restored the β-adrenergic response of ICaL, with the difference from basal current even exceeding that in wild-type mice (- 12.2 ± 2.9 pA/pF).We propose that by restoring basal ICaL, Gαi3 deficiency might contribute to the restoration of contractility in β1-tg mice, while maintaining attenuation of the ICaL response upon β-adrenergic stimulation protects against deleterious effects mediated by enhanced β-AR signalling. In contrast, restored and even enhanced ICaL response to β-adrenergic stimulation might contribute to detrimental effects of Gαi2 deficiency observed in β1-tg mice previously.
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Affiliation(s)
- Nour Katnahji
- Center of Pharmacology, Department II, University of Cologne and University Hospital Cologne, Gleueler Strasse 24, Cologne, 50931, Germany
| | - Jan Matthes
- Center of Pharmacology, Department II, University of Cologne and University Hospital Cologne, Gleueler Strasse 24, Cologne, 50931, Germany.
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2
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Kaplan A, El‐Samadi L, Zahreddine R, Amin G, Booz GW, Zouein FA. Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure. Acta Physiol (Oxf) 2025; 241:e70010. [PMID: 39960030 PMCID: PMC11831727 DOI: 10.1111/apha.70010] [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: 08/19/2024] [Revised: 01/12/2025] [Accepted: 01/20/2025] [Indexed: 02/20/2025]
Abstract
G protein-coupled receptor kinase 2 (GRK2) with its multidomain structure performs various crucial cellular functions under both normal and pathological conditions. Overexpression of GRK2 is linked to cardiovascular diseases, and its inhibition or deletion has been shown to be protective. The functions of GRK2 extend beyond G protein-coupled receptor (GPCR) signaling, influencing non-GPCR substrates as well. Increased GRK2 in heart failure (HF) initially may be protective but ultimately leads to maladaptive effects such as GPCR desensitization, insulin resistance, and apoptosis. The multifunctional nature of GRK2, including its action in hypertrophic gene expression, insulin signaling, and cardiac fibrosis, highlights its complex role in HF pathogenesis. Additionally, GRK2 is involved in mitochondrial biogenesis and lipid metabolism. GRK2 also regulates epinephrine secretion from the adrenal gland and its increase in circulating lymphocytes can be used to monitor HF status. Overall, GRK2 is a multifaceted protein with significant implications for HF and the regulation of GRK2 is crucial for understanding and treating cardiovascular diseases.
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Affiliation(s)
- Abdullah Kaplan
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Cardiology ClinicKemer Public HospitalAntalyaTurkey
| | - Lana El‐Samadi
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
| | - Rana Zahreddine
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
| | - Ghadir Amin
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - George W. Booz
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - Fouad A. Zouein
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
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3
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Parichatikanond W, Duangrat R, Kurose H, Mangmool S. Regulation of β-Adrenergic Receptors in the Heart: A Review on Emerging Therapeutic Strategies for Heart Failure. Cells 2024; 13:1674. [PMID: 39451192 PMCID: PMC11506672 DOI: 10.3390/cells13201674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/24/2024] [Accepted: 10/08/2024] [Indexed: 10/26/2024] Open
Abstract
The prolonged overstimulation of β-adrenergic receptors (β-ARs), a member of the G protein-coupled receptor (GPCR) family, causes abnormalities in the density and functionality of the receptor and contributes to cardiac dysfunctions, leading to the development and progression of heart diseases, especially heart failure (HF). Despite recent advancements in HF therapy, mortality and morbidity rates continue to be high. Treatment with β-AR antagonists (β-blockers) has improved clinical outcomes and reduced overall hospitalization and mortality rates. However, several barriers in the management of HF remain, providing opportunities to develop new strategies that focus on the functions and signal transduction of β-ARs involved in the pathogenesis of HF. As β-AR can signal through multiple pathways influenced by different receptor subtypes, expression levels, and signaling components such as G proteins, G protein-coupled receptor kinases (GRKs), β-arrestins, and downstream effectors, it presents a complex mechanism that could be targeted in HF management. In this narrative review, we focus on the regulation of β-ARs at the receptor, G protein, and effector loci, as well as their signal transductions in the physiology and pathophysiology of the heart. The discovery of potential ligands for β-AR that activate cardioprotective pathways while limiting off-target signaling is promising for the treatment of HF. However, applying findings from preclinical animal models to human patients faces several challenges, including species differences, the genetic variability of β-ARs, and the complexity and heterogeneity of humans. In this review, we also summarize recent updates and future research on the regulation of β-ARs in the molecular basis of HF and highlight potential therapeutic strategies for HF.
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Affiliation(s)
| | - Ratchanee Duangrat
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Hitoshi Kurose
- Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, Japan;
- Pharmacology for Life Sciences, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Supachoke Mangmool
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
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4
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Du X, Feng X, Ming Z, Kiriazis H. Cardiomyopathy characterizing and heart failure risk predicting by echocardiography and pathoanatomy in aged male mice. Physiol Rep 2024; 12:e70061. [PMID: 39411804 PMCID: PMC11480644 DOI: 10.14814/phy2.70061] [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: 07/23/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 10/20/2024] Open
Abstract
Correlation between echocardiographic and pathoanatomic variables and their prognostic value in murine cardiomyopathy models remain unknown. Using echocardiography, morphometrics, and survival monitoring, we characterized transgenic (TG) mice with dilated cardiomyopathy due to cardiac overexpression of β2-adrenoceptors focusing on predicting heart failure (HF) risk and HF mortality. In 12-month-old non-TG and TG mice, echocardiography was performed to determine left ventricular (LV) dimensions (d), wall thickness (h), and fractional shortening (FS). Animals were monitored for 3 months for survival. Organ weights and pathological events indicating left HF were determined. TG mice (n = 76) had reduced FS and enlarged LV, and 79% died of HF or likely arrhythmias during the follow-up period while all non-TG mice (n = 26) survived. These mice with left HF also had pulmonary congestion and hypertrophy/dilatation of the right ventricle (RV). Weights of lungs, RV, and atria were intercorrelated (r = 0.79-0.83) and also negatively correlated with FS × (h/d) index (r = -0.502 to -0.609). By FS × (h/d) tertiles, TG mice of low tertiles were identified with the highest mortality (96%) largely due to HF (76%). In conclusion, in aged cardiomyopathy mice a good correlation existed between echocardiographic and pathoanatomic variables. Echocardiography-derived LV function and remodeling were useful in identifying a subgroup of TG mice with a high risk of HF and HF fatality.
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Affiliation(s)
- Xiao‐Jun Du
- Department of Physiology and Pathophysiology, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anShaanxiChina
- Experimental CardiologyBaker Heart and Diabetes InstituteMelbourneVictoriaAustralia
| | - Xin‐Heng Feng
- Experimental CardiologyBaker Heart and Diabetes InstituteMelbourneVictoriaAustralia
- Present address:
Department of Cardiology and Institute of Vascular MedicinePeking University Third HospitalBeijingChina
| | - Zi‐Qiu Ming
- Experimental CardiologyBaker Heart and Diabetes InstituteMelbourneVictoriaAustralia
- Present address:
Dandenong NeurologyDandenongVictoriaAustralia
| | - Helen Kiriazis
- Experimental CardiologyBaker Heart and Diabetes InstituteMelbourneVictoriaAustralia
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5
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Du XJ, She G, Wu W, Deng XL. Coupling of β-adrenergic and Hippo pathway signaling: Implications for heart failure pathophysiology and metabolic therapy. Mitochondrion 2024; 78:101941. [PMID: 39122227 DOI: 10.1016/j.mito.2024.101941] [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: 03/20/2024] [Revised: 07/17/2024] [Accepted: 08/03/2024] [Indexed: 08/12/2024]
Abstract
Activation of the sympatho-β-adrenergic receptor (βAR) system is the hallmark of heart disease with adverse consequences that facilitate the onset and progression of heart failure (HF). Use of β-blocking drugs has become the front-line therapy for HF. Last decade has witnessed progress in research demonstrating a pivotal role of Hippo pathway in cardiomyopathy and HF. Clinical studies have revealed myocardial Hippo pathway activation/YAP-TEAD1 inactivation in several types of human cardiomyopathy. Experimental activation of cardiac Hippo signaling or inhibition of YAP-TEAD1 have been shown to leads dilated cardiomyopathy with severe mitochondrial dysfunction and metabolic reprogramming. Studies have also convincingly shown that stimulation of βAR activates cardiac Hippo pathway with inactivation of the down-stream effector molecules YAP/TAZ. There is strong evidence for the adverse consequences of the βAR-Hippo signaling leading to HF. In addition to promoting cardiomyocyte death and fibrosis, recent progress is the demonstration of mitochondrial dysfunction and metabolic reprogramming mediated by βAR-Hippo pathway signaling. Activation of cardiac βAR-Hippo signaling is potent in downregulating a range of mitochondrial and metabolic genes, whereas expression of pro-inflammatory and pro-fibrotic factors are upregulated. Coupling of βAR-Hippo pathway signaling is mediated by several kinases, mechanotransduction and/or Ca2+ signaling, and can be blocked by β-antagonists. Demonstration of the converge of βAR signaling and Hippo pathway bears implications for a better understanding on the role of enhanced sympathetic nervous activity, efficacy of β-antagonists, and metabolic therapy targeting this pathway in HF. In this review we summarize the progress and discuss future research directions in this field.
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Affiliation(s)
- Xiao-Jun Du
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, Shaanxi 710061, China; Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia,.
| | - Gang She
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, Shaanxi 710061, China
| | - Wei Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, Shaanxi 710061, China; Department of Cardiology, Shaanxi Provincial Hospital and the Third Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiu-Ling Deng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, Shaanxi 710061, China
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6
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Brand T, Lukannek AK, Jahns V, Jahns R, Lorenz K. From "contraindicated" to "first line" - Current mechanistic insights beyond canonical β-receptor signaling. Curr Opin Pharmacol 2024; 76:102458. [PMID: 38636195 DOI: 10.1016/j.coph.2024.102458] [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: 03/14/2024] [Accepted: 03/27/2024] [Indexed: 04/20/2024]
Abstract
β-blockers are a solid pillar in the treatment of cardiovascular diseases. However, they are highly discussed regarding effectiveness for certain indications and side-effects. Even though there are up to 20 licensed compounds, only four are used for heart failure (HF) therapy. On the receptor level several key characteristics seem to influence the clinical outcome: subtype selectivity, antagonistic vs (inverse/biased) agonistic properties and -in particular- ancillary capacities. On a molecular level, divergent and novel signaling patterns are being identified and extra-cardiac effects on e.g. inflammation, metabolism and oxidative stress are highlighted. This review discusses different well-known and newly discovered characteristics that need to be considered for HF therapy and in the context of co-morbidities.
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Affiliation(s)
- Theresa Brand
- Institute of Pharmacology and Toxicology, University of Würzburg, Germany
| | | | - Valérie Jahns
- Institute of Pharmacology and Toxicology, University of Würzburg, Germany
| | - Roland Jahns
- Interdisciplinary Bank of Biological Materials and Data Würzburg (ibdw), University Hospital Würzburg, Germany
| | - Kristina Lorenz
- Institute of Pharmacology and Toxicology, University of Würzburg, Germany; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Cardiovascular Pharmacology, Dortmund, Germany.
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7
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Sun X, Han Y, Yu Y, Chen Y, Dong C, Lv Y, Qu H, Fan Z, Yu Y, Sang Y, Tang W, Liu Y, Ju J, Zhao D, Bai Y. Overexpressing of the GIPC1 protects against pathological cardiac remodelling. Eur J Pharmacol 2024; 971:176488. [PMID: 38458410 DOI: 10.1016/j.ejphar.2024.176488] [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: 03/16/2023] [Revised: 03/02/2024] [Accepted: 03/06/2024] [Indexed: 03/10/2024]
Abstract
OBJECTIVE Pathological cardiac remodelling, including cardiac hypertrophy and fibrosis, is a key pathological process in the development of heart failure. However, effective therapeutic approaches are limited. The β-adrenergic receptors are pivotal signalling molecules in regulating cardiac function. G-alpha interacting protein (GAIP)-interacting protein, C-terminus 1 (GIPC1) is a multifunctional scaffold protein that directly binds to the C-terminus of β1-adrenergic receptor (β1-adrenergic receptor). However, little is known about its roles in heart function. Therefore, we investigated the role of GIPC1 in cardiac remodelling and its underlying molecular mechanisms. METHODS Pathological cardiac remodelling in mice was established via intraperitoneal injection of isoprenaline for 14 d or transverse aortic constriction surgery for 8 weeks. Myh6-driving cardiomyocyte-specific GIPC1 conditional knockout (GIPC1 cKO) mice and adeno-associated virus 9 (AAV9)-mediated GIPC1 overexpression mice were used. The effect of GIPC1 on cardiac remodelling was assessed using echocardiographic, histological, and biochemical analyses. RESULTS GIPC1 expression was consistently reduced in the cardiac remodelling model. GIPC1 cKO mice exhibited spontaneous abnormalities, including cardiac hypertrophy, fibrosis, and systolic dysfunction. In contrast, AAV9-mediated GIPC1 overexpression in the heart attenuated isoproterenol-induced pathological cardiac remodelling in mice. Mechanistically, GIPC1 interacted with the β1-adrenergic receptor and stabilised its expression by preventing its ubiquitination and degradation, maintaining the balance of β1-adrenergic receptor/β2-adrenergic receptor, and inhibiting hyperactivation of the mitogen-activated protein kinase signalling pathway. CONCLUSIONS These results suggested that GIPC1 plays a cardioprotective role and is a promising therapeutic target for the treatment of cardiac remodelling and heart failure.
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Affiliation(s)
- Xi Sun
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China; Department of Scientific Research, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yanna Han
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yahan Yu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yujie Chen
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Chaorun Dong
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yuan Lv
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Huan Qu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Zheyu Fan
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yi Yu
- Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China
| | - Yaru Sang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Wenxia Tang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yu Liu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jiaming Ju
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Dan Zhao
- Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China.
| | - Yunlong Bai
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Joint International Research Laboratory of Cardiovascular Medicine, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.
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8
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Schröper T, Mehrkens D, Leiss V, Tellkamp F, Engelhardt S, Herzig S, Birnbaumer L, Nürnberg B, Matthes J. Protective effects of Gα i3 deficiency in a murine heart-failure model of β 1-adrenoceptor overexpression. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2401-2420. [PMID: 37843590 PMCID: PMC10933181 DOI: 10.1007/s00210-023-02751-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 09/26/2023] [Indexed: 10/17/2023]
Abstract
We have shown that in murine cardiomyopathy caused by overexpression of the β1-adrenoceptor, Gαi2-deficiency is detrimental. Given the growing evidence for isoform-specific Gαi-functions, we now examined the consequences of Gαi3 deficiency in the same heart-failure model. Mice overexpressing cardiac β1-adrenoceptors with (β1-tg) or without Gαi3-expression (β1-tg/Gαi3-/-) were compared to C57BL/6 wildtypes and global Gαi3-knockouts (Gαi3-/-). The life span of β1-tg mice was significantly shortened but improved when Gαi3 was lacking (95% CI: 592-655 vs. 644-747 days). At 300 days of age, left-ventricular function and survival rate were similar in all groups. At 550 days of age, β1-tg but not β1-tg/Gαi3-/- mice displayed impaired ejection fraction (35 ± 18% vs. 52 ± 16%) compared to wildtype (59 ± 4%) and Gαi3-/- mice (60 ± 5%). Diastolic dysfunction of β1-tg mice was prevented by Gαi3 deficiency, too. The increase of ANP mRNA levels and ventricular fibrosis observed in β1-tg hearts was significantly attenuated in β1-tg/Gαi3-/- mice. Transcript levels of phospholamban, ryanodine receptor 2, and cardiac troponin I were similar in all groups. However, Western blots and phospho-proteomic analyses showed that in β1-tg, but not β1-tg/Gαi3-/- ventricles, phospholamban protein was reduced while its phosphorylation increased. Here, we show that in mice overexpressing the cardiac β1-adrenoceptor, Gαi3 deficiency slows or even prevents cardiomyopathy and increases shortened life span. Previously, we found Gαi2 deficiency to aggravate cardiac dysfunction and mortality in the same heart-failure model. Our findings indicate isoform-specific interventions into Gi-dependent signaling to be promising cardio-protective strategies.
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Affiliation(s)
- Tobias Schröper
- Center of Pharmacology, Department II, University of Cologne and University Hospital Cologne, Cologne, Germany
- Department of Internal Medicine III, University Hospital of Cologne, Cologne, Germany and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Dennis Mehrkens
- Department of Internal Medicine III, University Hospital of Cologne, Cologne, Germany and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Centre for Molecular Medicine Cologne, CMMC, University of Cologne, Cologne, Germany
| | - Veronika Leiss
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute for Experimental and Clinical Pharmacology and Pharmacogenomics, and Interfaculty Centre for Pharmacogenomics and Drug Research, Eberhard Karls Universität, Tübingen, Germany
| | - Frederik Tellkamp
- CECAD Research Centre Institute for Genetics, University of Cologne, Cologne, Germany
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technische Universität München, Munich, Germany
| | - Stefan Herzig
- Center of Pharmacology, Department II, University of Cologne and University Hospital Cologne, Cologne, Germany
- TH Köln-University of Applied Sciences, Cologne, Germany
| | - Lutz Birnbaumer
- Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA
- Institute of Biomedical Research, School of Medical Sciences, Catholic University of Buenos Aires, Buenos Aires, Argentina
| | - Bernd Nürnberg
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute for Experimental and Clinical Pharmacology and Pharmacogenomics, and Interfaculty Centre for Pharmacogenomics and Drug Research, Eberhard Karls Universität, Tübingen, Germany
| | - Jan Matthes
- Center of Pharmacology, Department II, University of Cologne and University Hospital Cologne, Cologne, Germany.
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9
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Steinberg SF. Redox and proteolytic regulation of cardiomyocyte β 1-adrenergic receptors - a novel paradigm for the regulation of catecholamine responsiveness in the heart. Front Immunol 2023; 14:1306467. [PMID: 38111579 PMCID: PMC10726029 DOI: 10.3389/fimmu.2023.1306467] [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: 10/03/2023] [Accepted: 11/21/2023] [Indexed: 12/20/2023] Open
Abstract
Conventional models view β1-adrenergic receptors (β1ARs) as full-length proteins that activate signaling pathways that influence contractile function and ventricular remodeling - and are susceptible to agonist-dependent desensitization. This perspective summarizes recent studies from my laboratory showing that post-translational processing of the β1-adrenergic receptor N-terminus results in the accumulation of both full-length and N-terminally truncated forms of the β1AR that differ in their signaling properties. We also implicate oxidative stress and β1AR cleavage by elastase as two novel mechanisms that would (in the setting of cardiac injury or inflammation) lead to altered or decreased β1AR responsiveness.
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Affiliation(s)
- Susan F. Steinberg
- Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, United States
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10
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Abdellatif M, Rainer PP, Sedej S, Kroemer G. Hallmarks of cardiovascular ageing. Nat Rev Cardiol 2023; 20:754-777. [PMID: 37193857 DOI: 10.1038/s41569-023-00881-3] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/21/2023] [Indexed: 05/18/2023]
Abstract
Normal circulatory function is a key determinant of disease-free life expectancy (healthspan). Indeed, pathologies affecting the cardiovascular system, which are growing in prevalence, are the leading cause of global morbidity, disability and mortality, whereas the maintenance of cardiovascular health is necessary to promote both organismal healthspan and lifespan. Therefore, cardiovascular ageing might precede or even underlie body-wide, age-related health deterioration. In this Review, we posit that eight molecular hallmarks are common denominators in cardiovascular ageing, namely disabled macroautophagy, loss of proteostasis, genomic instability (in particular, clonal haematopoiesis of indeterminate potential), epigenetic alterations, mitochondrial dysfunction, cell senescence, dysregulated neurohormonal signalling and inflammation. We also propose a hierarchical order that distinguishes primary (upstream) from antagonistic and integrative (downstream) hallmarks of cardiovascular ageing. Finally, we discuss how targeting each of the eight hallmarks might be therapeutically exploited to attenuate residual cardiovascular risk in older individuals.
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Affiliation(s)
- Mahmoud Abdellatif
- Department of Cardiology, Medical University of Graz, Graz, Austria.
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
- BioTechMed Graz, Graz, Austria.
| | - Peter P Rainer
- Department of Cardiology, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
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11
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Fernandes S, Oatman E, Weinberger J, Dixon A, Osei-Owusu P, Hou S. The susceptibility of cardiac arrhythmias after spinal cord crush injury in rats. Exp Neurol 2022; 357:114200. [PMID: 35952765 PMCID: PMC9801389 DOI: 10.1016/j.expneurol.2022.114200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/03/2022] [Accepted: 08/03/2022] [Indexed: 01/03/2023]
Abstract
High-level spinal cord injury (SCI) often interrupts supraspinal regulation of sympathetic input to the heart. Although it is known that dysregulated autonomic control increases the risk for cardiac disorders, the mechanisms mediating SCI-induced arrhythmias are poorly understood. Here, we employed a rat model of complete spinal cord crush injury at the 2nd/3rd thoracic (T2/3) level to investigate cardiac rhythm disorders resulting from SCI. Rats with T9 injury and naïve animals served as two controls. Four weeks after SCI, rats were implanted with a radio-telemetric device for electrocardiogram and blood pressure monitoring. During 24-h recordings, heart rate variability in rats with T2/3 but not T9 injury exhibited a significant reduction in the time domain, and a decrease in power at low frequency but increased power at high frequency in the frequency domain which indicates reduced sympathetic and increased parasympathetic outflow to the heart. Pharmacological blockade of the sympathetic or parasympathetic branches confirmed the imbalance of cardiac autonomic control. Activation of sympatho-vagal input during the induction of autonomic dysreflexia by colorectal distention triggered various severe arrhythmic events in T2/3 injured rats. Meanwhile, intravenous infusion of the β1-adrenergic receptor agonist, dobutamine, caused greater incidence of arrhythmias in rats with T2/3 injury than naïve and T9 injured controls. Together, the results indicate that high-level SCI increases the susceptibility to developing cardiac arrhythmias likely owing to compromised autonomic homeostasis. The T2/3 crush model is appropriate for studying abnormal cardiac electrophysiology resulting from SCI.
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Affiliation(s)
- Silvia Fernandes
- Marion Murray Spinal Cord Research Center, Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Emily Oatman
- Marion Murray Spinal Cord Research Center, Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Jeremy Weinberger
- Marion Murray Spinal Cord Research Center, Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Alethia Dixon
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Patrick Osei-Owusu
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
| | - Shaoping Hou
- Marion Murray Spinal Cord Research Center, Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
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12
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Steinberg SF. N-Tertaining a New Signaling Paradigm for the Cardiomyocyte β 1 -Adrenergic Receptor. J Cardiovasc Pharmacol 2022; 80:328-333. [PMID: 35099166 PMCID: PMC9170829 DOI: 10.1097/fjc.0000000000001194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 11/20/2021] [Indexed: 01/31/2023]
Abstract
ABSTRACT β 1 -adrenergic receptors (β 1 ARs) are the principle mediators of catecholamine actions in cardiomyocytes. β 1 ARs rapidly adjust cardiac output and provide short-term hemodynamic support for the failing heart by activating a Gs-adenylyl cyclase pathway that increases 3'-5'-cyclic adenosine monophosphate and leads to the activation of protein kinase A and the phosphorylation of substrates involved in excitation-contraction coupling. However, chronic persistent β 1 AR activation in the setting of heart failure leads to a spectrum of maladaptive changes that contribute to the evolution of heart failure. The molecular basis for β 1 AR-driven maladaptive responses remains uncertain because chronic persistent β 1 AR activation has been linked to the activation of both proapoptotic and antiapoptotic signaling pathways. Of note, studies to date have been predicated on the assumption that β 1 ARs signal exclusively as full-length receptor proteins. Our recent studies show that β 1 ARs are detected as both full-length and N-terminally truncated species in cardiomyocytes, that N-terminal cleavage is regulated by O-glycan modifications at specific sites on the β 1 AR N-terminus, and that N-terminally truncated β 1 ARs remain signaling competent, but their signaling properties differ from those of the full-length β 1 AR. The N-terminally truncated form of the β 1 AR constitutively activates the protein kinase B signaling pathway and confers protection against doxorubicin-dependent apoptosis in cardiomyocytes. These studies identify a novel signaling paradigm for the β 1 AR, implicating the N-terminus as a heretofore-unrecognized structural determinant of β 1 AR responsiveness that could be pharmacologically targeted for therapeutic advantage.
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13
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Wei W, Smrcka AV. Subcellular β-Adrenergic Receptor Signaling in Cardiac Physiology and Disease. J Cardiovasc Pharmacol 2022; 80:334-341. [PMID: 35881897 PMCID: PMC9452480 DOI: 10.1097/fjc.0000000000001324] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 06/29/2022] [Indexed: 01/31/2023]
Abstract
ABSTRACT Adrenergic receptors are critical regulators of cardiac function with profound effects on cardiac output during sympathetic stimulation. Chronic stimulation of the adrenergic system of the heart under conditions of cardiac stress leads to cardiac dysfunction, hypertrophy, and ultimately failure. Emerging data have revealed that G protein-coupled receptors in intracellular compartments are functionally active and regulate distinct cellular processes from those at the cell surface. β2 adrenergic receptors internalize onto endosomes in various cell types where they have recently been shown to continue to stimulate cAMP production to selectively regulate gene expression. Other studies have identified β1 adrenergic receptors at the nuclear envelope and the Golgi apparatus. Here, we discuss data on signaling by β1 and β2 adrenergic receptors in the heart and the possible influence of their subcellular locations on their divergent physiological functions in cardiac myocytes and in cardiac pathology. Understanding the relative roles of these receptors at these locations could have a significant impact on pharmacological targeting of these receptors for the treatment of heart failure and cardiac diseases.
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Affiliation(s)
- Wenhui Wei
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI
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14
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Xu R, Fu J, Hu Y, Yang X, Tao X, Chen L, Huang K, Fu Q. Roflumilast-Mediated Phosphodiesterase 4D Inhibition Reverses Diabetes-Associated Cardiac Dysfunction and Remodeling: Effects Beyond Glucose Lowering. Diabetes 2022; 71:1660-1678. [PMID: 35594380 DOI: 10.2337/db21-0898] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 05/02/2022] [Indexed: 11/13/2022]
Abstract
Patients with type 2 diabetes have a substantial risk of developing cardiovascular disease. Phosphodiesterase 4 (PDE4) dysregulation is of pathophysiological importance in metabolic disorders. For determination of the role of PDE4 in diabetic cardiac dysfunction, mice fed with a high-fat diet (HFD) were treated by pharmacological inhibition of PDE4 or cardiac specific knocking down of PDE4D. Mice on HFD developed diabetes and cardiac dysfunction with increased cardiac PDE4D5 expression. PDE4 inhibitor roflumilast can reverse hyperglycemia and cardiac dysfunction, accompanied by the decrease of PDE4D expression and increase of muscle specific miRNA miR-1 level in hearts. Either cardiac specific PDE4D knockdown or miR-1 overexpression significantly reversed cardiac dysfunction in HFD mice, despite persistence of hyperglycemia. Findings of gain- and loss-of-function studies of PDE4D in cardiomyocytes indicated that inhibition of insulin-induced PDE4D protected cardiac hypertrophy by preserving miR-1 expression in cardiomyocytes through promoting cAMP-CREB-Sirt1 signaling-induced SERCA2a expression. We further revealed that insulin also induced PDE4D expression in cardiac fibroblasts, which causes cardiac fibrosis through TGF-β1 signaling-mediated miR-1 reduction. Importantly, the expression of PDE4D5 was increased in human failing hearts of individuals with diabetes. These studies elucidate a novel mechanism by which hyperinsulinemia-induced cardiac PDE4D expression contributes to diabetic cardiac remodeling through reducing the expression of miR-1 and upregulation of miR-1 target hypertrophy and fibrosis-associated genes. Our study suggests a therapeutic potential of PDE4 inhibitor roflumilast in preventing or treating cardiac dysfunction in diabetes in addition to lowering glucose.
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Affiliation(s)
- Rui Xu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Jing Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Yuting Hu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyan Yang
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Xiang Tao
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Long Chen
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Huang
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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15
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Dorn Ii GW. Neurohormonal Connections with Mitochondria in Cardiomyopathy and Other Diseases. Am J Physiol Cell Physiol 2022; 323:C461-C477. [PMID: 35759434 PMCID: PMC9363002 DOI: 10.1152/ajpcell.00167.2022] [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] [Indexed: 11/22/2022]
Abstract
Neurohormonal signaling and mitochondrial dynamism are seemingly distinct processes that are almost ubiquitous among multicellular organisms. Both of these processes are regulated by GTPases, and disturbances in either can provoke disease. Here, inconspicuous pathophysiological connectivity between neurohormonal signaling and mitochondrial dynamism is reviewed in the context of cardiac and neurological syndromes. For both processes, greater understanding of basic mechanisms has evoked a reversal of conventional pathophysiological concepts. Thus, neurohormonal systems induced in, and previously thought to be critical for, cardiac functioning in heart failure are now pharmaceutically interrupted as modern standard of care. And, mitochondrial abnormalities in neuropathies that were originally attributed to an imbalance between mitochondrial fusion and fission are increasingly recognized as an interruption of axonal mitochondrial transport. The data are presented in a historical context to provided insight into how scientific thought has evolved and to foster an appreciation for how seemingly different areas of investigation can converge. Finally, some theoretical notions are presented to explain how different molecular and functional defects can evoke tissue-specific disease.
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Affiliation(s)
- Gerald W Dorn Ii
- Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
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16
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Assessment of the epi-pericardial fibrotic substrate by collagen-targeted probes. Sci Rep 2022; 12:5702. [PMID: 35383230 PMCID: PMC8983671 DOI: 10.1038/s41598-022-08688-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/08/2022] [Indexed: 11/29/2022] Open
Abstract
The identification of the fibrotic arrhythmogenic substrate as a means of improving the diagnosis and prediction of atrial fibrillation has been a focus of research for many years. The relationship between the degree of atrial fibrosis as a major component of atrial cardiomyopathy and the recurrence of arrhythmia after AF ablation can correlate. While the focus in identification and characterisation of this substrate has been centred on the atrial wall and the evaluation of atrial scar and extracellular matrix (ECM) expansion by late gadolinium-enhancement (LGE) on cardiac magnetic resonance imaging (CMRI), LGE cannot visualise diffuse fibrosis and diffuse extravasation of gadolinium. The atrial pericardium is a fine avascular fibrous membranous sac that encloses the atrial wall, which can undergo remodelling leading to atrial disease and AF. Nevertheless, little attention has been given to the detection of its fibrocalcification, impact on arrhythmogenesis and, most importantly, on the potential prothrombotic role of epi-pericardial remodelling in generation of emboli. We have recently reported that tracers against collagen I and IV can provide a direct assessment of the ECM, and thus can estimate fibrotic burden with high sensitivity. Here, we show the ability of these optical tracers to identify epi-pericardial fibrosis, as well as to demonstrate subtle interstitial fibrosis of the atrial wall in a mouse model of beta-2-adrenergic receptor (β2-AR) cardiac overexpression.
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17
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Abd Alla J, Quitterer U. The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart. Cells 2022; 11:cells11040654. [PMID: 35203304 PMCID: PMC8869954 DOI: 10.3390/cells11040654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/08/2022] [Accepted: 02/11/2022] [Indexed: 02/04/2023] Open
Abstract
The RAF kinase inhibitor protein, RKIP, is a dual inhibitor of the RAF1 kinase and the G protein-coupled receptor kinase 2, GRK2. By inhibition of the RAF1-MAPK (mitogen-activated protein kinase) pathway, RKIP acts as a beneficial tumour suppressor. By inhibition of GRK2, RKIP counteracts GRK2-mediated desensitisation of G protein-coupled receptor (GPCR) signalling. GRK2 inhibition is considered to be cardioprotective under conditions of exaggerated GRK2 activity such as heart failure. However, cardioprotective GRK2 inhibition and pro-survival RAF1-MAPK pathway inhibition counteract each other, because inhibition of the pro-survival RAF1-MAPK cascade is detrimental for the heart. Therefore, the question arises, what is the net effect of these apparently divergent functions of RKIP in vivo? The available data show that, on one hand, GRK2 inhibition promotes cardioprotective signalling in isolated cardiomyocytes. On the other hand, inhibition of the pro-survival RAF1-MAPK pathway by RKIP deteriorates cardiomyocyte viability. In agreement with cardiotoxic effects, endogenous RKIP promotes cardiac fibrosis under conditions of cardiac stress, and transgenic RKIP induces heart dysfunction. Supported by next-generation sequencing (NGS) data of the RKIP-induced cardiac transcriptome, this review provides an overview of different RKIP functions and explains how beneficial GRK2 inhibition can go awry by RAF1-MAPK pathway inhibition. Based on RKIP studies, requirements for the development of a cardioprotective GRK2 inhibitor are deduced.
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Affiliation(s)
- Joshua Abd Alla
- Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland;
| | - Ursula Quitterer
- Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland;
- Department of Medicine, Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
- Correspondence: ; Tel.: +41-44-632-9801
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18
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Du X. Sympatho-adrenergic mechanisms in heart failure: new insights into pathophysiology. MEDICAL REVIEW (BERLIN, GERMANY) 2021; 1:47-77. [PMID: 37724075 PMCID: PMC10388789 DOI: 10.1515/mr-2021-0007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/02/2021] [Indexed: 09/20/2023]
Abstract
The sympathetic nervous system is activated in the setting of heart failure (HF) to compensate for hemodynamic instability. However, acute sympathetic surge or sustained high neuronal firing rates activates β-adrenergic receptor (βAR) signaling contributing to myocardial remodeling, dysfunction and electrical instability. Thus, sympatho-βAR activation is regarded as a hallmark of HF and forms pathophysiological basis for β-blocking therapy. Building upon earlier research findings, studies conducted in the recent decades have significantly advanced our understanding on the sympatho-adrenergic mechanism in HF, which forms the focus of this article. This review notes recent research progress regarding the roles of cardiac β2AR or α1AR in the failing heart, significance of β1AR-autoantibodies, and βAR signaling through G-protein independent signaling pathways. Sympatho-βAR regulation of immune cells or fibroblasts is specifically discussed. On the neuronal aspects, knowledge is assembled on the remodeling of sympathetic nerves of the failing heart, regulation by presynaptic α2AR of NE release, and findings on device-based neuromodulation of the sympathetic nervous system. The review ends with highlighting areas where significant knowledge gaps exist but hold promise for new breakthroughs.
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Affiliation(s)
- Xiaojun Du
- Faculty of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, 76 West Yanta Road, Xi’an710061, Shaanxi, China
- Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC3004, Australia
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19
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Ezeani M, Noor A, Alt K, Lal S, Donnelly PS, Hagemeyer CE, Niego B. Collagen-Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis. J Am Heart Assoc 2021; 10:e022139. [PMID: 34514814 PMCID: PMC8649514 DOI: 10.1161/jaha.121.022139] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Cardiac fibrosis is the excessive deposition of extracellular matrix in the heart, triggered by a cardiac insult, aging, genetics, or environmental factors. Molecular imaging of the cardiac extracellular matrix with targeted probes could improve diagnosis and treatment of heart disease. However, although this technology has been used to demonstrate focal scarring arising from myocardial infarction, its capacity to demonstrate extracellular matrix expansion and diffuse cardiac fibrosis has not been assessed. Methods and Results Here, we report the use of collagen-targeted peptides labeled with near-infrared fluorophores for the detection of diffuse cardiac fibrosis in the β2-AR (β-2-adrenergic receptor) overexpressing mouse model and in ischemic human hearts. Two approaches were evaluated, the first based on a T peptide that binds matrix metalloproteinase-2-proteolyzed collagen IV, and the second on the cyclic peptide EP-3533, which targets collagen I. The systemic and cardiac uptakes of both peptides (intravenously administered) were quantified ex vivo by near-infrared imaging of whole organs, tissue sections, and heart lysates. The peptide accumulation profiles corresponded to an immunohistochemically-validated increase in collagen types I and IV in hearts of transgenic mice versus littermate controls. The T peptide could encouragingly demonstrate both the intermediate (7 months old) and severe (11 months old) cardiomyopathic phenotypes. Co-immunostainings of fluorescent peptides and collagens, as well as reduced collagen binding of a control peptide, confirmed the collagen specificity of the tracers. Qualitative analysis of heart samples from patients with ischemic cardiomyopathy compared with nondiseased donors supported the collagen-enhancement capabilities of these peptides also in the clinical settings. Conclusions Together, these observations demonstrate the feasibility and translation potential of molecular imaging with collagen-binding peptides for noninvasive imaging of diffuse cardiac fibrosis.
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Affiliation(s)
- Martin Ezeani
- NanoBiotechnology Laboratory Australian Centre for Blood Diseases Central Clinical School Monash University Melbourne Australia
| | - Asif Noor
- School of Chemistry Bio21 Molecular Science and Biotechnology Institute University of Melbourne Australia
| | - Karen Alt
- NanoTheranostics Laboratory Australian Centre for Blood Diseases Central Clinical School Monash University Melbourne Australia
| | - Sean Lal
- School of Medical Sciences Faculty of Medicine and Health University of Sydney Australia
| | - Paul S Donnelly
- School of Chemistry Bio21 Molecular Science and Biotechnology Institute University of Melbourne Australia
| | - Christoph E Hagemeyer
- NanoBiotechnology Laboratory Australian Centre for Blood Diseases Central Clinical School Monash University Melbourne Australia
| | - Be'eri Niego
- NanoBiotechnology Laboratory Australian Centre for Blood Diseases Central Clinical School Monash University Melbourne Australia
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20
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Guitart-Mampel M, Urquiza P, Borges JI, Lymperopoulos A, Solesio ME. Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function. Cells 2021; 10:1552. [PMID: 34205363 PMCID: PMC8235589 DOI: 10.3390/cells10061552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/08/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)-particularly βARs-play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.
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Affiliation(s)
- Mariona Guitart-Mampel
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
| | - Pedro Urquiza
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
| | - Jordana I. Borges
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Anastasios Lymperopoulos
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Maria E. Solesio
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
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21
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Aimo A, Pelliccia F, Panichella G, Vergaro G, Barison A, Passino C, Emdin M, Camici PG. Indications of beta-adrenoceptor blockers in Takotsubo syndrome and theoretical reasons to prefer agents with vasodilating activity. Int J Cardiol 2021; 333:45-50. [PMID: 33667578 DOI: 10.1016/j.ijcard.2021.02.074] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 12/26/2022]
Abstract
Takotsubo syndrome (TTS) is estimated to account for 1-3% of all patients presenting with suspected ST-segment elevation myocardial infarction. A sudden surge in sympathetic nervous system is considered the cause of TTS. Nonetheless, no specific recommendations have been provided regarding β-blocking therapy. Apart from specific contra-indications (severe LV dysfunction, hypotension, bradycardia and corrected QT interval >500 ms), treatment with a β-blocker seems reasonable until full recovery of LV ejection fraction, though evidence is limited to a few animal studies, case reports or observational studies. In this review, we will reappraise the rationale for β-blocker therapy in TTS and speculate on the pathophysiologic basis for preferring non-selective agents with vasodilating activity over β1-selective drugs.
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Affiliation(s)
- Alberto Aimo
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy; Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
| | | | | | - Giuseppe Vergaro
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy; Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Andrea Barison
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy; Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Claudio Passino
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy; Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Michele Emdin
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy; Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Paolo G Camici
- San Raffaele Hospital and Vita Salute University, Milan, Italy
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22
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Why Do We Not Assess Sympathetic Nervous System Activity in Heart Failure Management: Might GRK2 Serve as a New Biomarker? Cells 2021; 10:cells10020457. [PMID: 33669936 PMCID: PMC7924864 DOI: 10.3390/cells10020457] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/11/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) represents the end-stage condition of several structural and functional cardiovascular diseases, characterized by reduced myocardial pump function and increased pressure load. The dysregulation of neurohormonal systems, especially the hyperactivity of the cardiac adrenergic nervous system (ANS), constitutes a hallmark of HF and exerts a pivotal role in its progression. Indeed, it negatively affects patients’ prognosis, being associated with high morbidity and mortality rates, with a tremendous burden on global healthcare systems. To date, all the techniques proposed to assess the cardiac sympathetic nervous system are burdened by intrinsic limits that hinder their implementation in clinical practice. Several biomarkers related to ANS activity, which may potentially support the clinical management of such a complex syndrome, are slow to be implemented in the routine practice for several limitations due to their assessment and clinical impact. Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2) levels reflect myocardial β-adrenergic receptor function in HF and have been shown to add independent prognostic information related to ANS overdrive. In the present manuscript, we provide an overview of the techniques currently available to evaluate cardiac ANS in HF and future perspectives in this field of relevant scientific and clinical interest.
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Liu Y, Chen J, Fontes SK, Bautista EN, Cheng Z. Physiological And Pathological Roles Of Protein Kinase A In The Heart. Cardiovasc Res 2021; 118:386-398. [PMID: 33483740 DOI: 10.1093/cvr/cvab008] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/30/2020] [Accepted: 01/08/2021] [Indexed: 12/21/2022] Open
Abstract
Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind β-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signaling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases.
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Affiliation(s)
- Yuening Liu
- Department of Pharmaceutical Sciences, Washington State University, PBS 423, 412 E. Spokane Falls Blvd, ., Spokane, WA, 99202-2131, USA
| | - Jingrui Chen
- Department of Pharmaceutical Sciences, Washington State University, PBS 423, 412 E. Spokane Falls Blvd, ., Spokane, WA, 99202-2131, USA
| | - Shayne K Fontes
- Department of Pharmaceutical Sciences, Washington State University, PBS 423, 412 E. Spokane Falls Blvd, ., Spokane, WA, 99202-2131, USA
| | - Erika N Bautista
- Department of Pharmaceutical Sciences, Washington State University, PBS 423, 412 E. Spokane Falls Blvd, ., Spokane, WA, 99202-2131, USA
| | - Zhaokang Cheng
- Department of Pharmaceutical Sciences, Washington State University, PBS 423, 412 E. Spokane Falls Blvd, ., Spokane, WA, 99202-2131, USA
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Borovac JA, D'Amario D, Bozic J, Glavas D. Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers. World J Cardiol 2020; 12:373-408. [PMID: 32879702 PMCID: PMC7439452 DOI: 10.4330/wjc.v12.i8.373] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/19/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.
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Affiliation(s)
- Josip Anđelo Borovac
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
| | - Domenico D'Amario
- Department of Cardiovascular and Thoracic Sciences, IRCCS Fondazione Policlinico A. Gemelli, Universita Cattolica Sacro Cuore, Rome 00168, Italy
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Duska Glavas
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
- Clinic for Cardiovascular Diseases, University Hospital of Split, Split 21000, Croatia
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Tibenska V, Benesova A, Vebr P, Liptakova A, Hejnová L, Elsnicová B, Drahota Z, Hornikova D, Galatík F, Kolar D, Vybiral S, Alánová P, Novotný J, Kolar F, Novakova O, Zurmanova JM. Gradual cold acclimation induces cardioprotection without affecting β-adrenergic receptor-mediated adenylyl cyclase signaling. J Appl Physiol (1985) 2020; 128:1023-1032. [DOI: 10.1152/japplphysiol.00511.2019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Novel strategies are needed that can stimulate endogenous signaling pathways to protect the heart from myocardial infarction. The present study tested the hypothesis that appropriate regimen of cold acclimation (CA) may provide a promising approach for improving myocardial resistance to ischemia/reperfusion (I/R) injury without negative side effects. We evaluated myocardial I/R injury, mitochondrial swelling, and β-adrenergic receptor (β-AR)-adenylyl cyclase-mediated signaling. Male Wistar rats were exposed to CA (8°C, 8 h/day for a week, followed by 4 wk at 8°C for 24 h/day), while the recovery group (CAR) was kept at 24°C for an additional 2 wk. The myocardial infarction induced by coronary occlusion for 20 min followed by 3-h reperfusion was reduced from 56% in controls to 30% and 23% after CA and CAR, respectively. In line, the rate of mitochondrial swelling at 200 μM Ca2+ was decreased in both groups. Acute administration of metoprolol decreased infarction in control group and did not affect the CA-elicited cardiprotection. Accordingly, neither β1-AR-Gsα-adenylyl cyclase signaling, stimulated with specific ligands, nor p-PKA/PKA ratios were affected after CA or CAR. Importantly, Western blot and immunofluorescence analyses revealed β2- and β3-AR protein enrichment in membranes in both experimental groups. We conclude that gradual cold acclimation results in a persisting increase of myocardial resistance to I/R injury without hypertension and hypertrophy. The cardioprotective phenotype is associated with unaltered adenylyl cyclase signaling and increased mitochondrial resistance to Ca2+-overload. The potential role of upregulated β2/β3-AR pathways remains to be elucidated. NEW & NOTEWORTHY We present a new model of mild gradual cold acclimation increasing tolerance to myocardial ischemia/reperfusion injury without hypertension and hypertrophy. Cardioprotective phenotype is accompanied by unaltered adenylyl cyclase signaling and increased mitochondrial resistance to Ca2+-overload. The potential role of upregulated β2/β3-adrenoreceptor activation is considered. These findings may stimulate the development of novel preventive and therapeutic strategies against myocardial ischemia/reperfusion injury.
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Affiliation(s)
- V. Tibenska
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - A. Benesova
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - P. Vebr
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - A. Liptakova
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - L. Hejnová
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - B. Elsnicová
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Z. Drahota
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - D. Hornikova
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - F. Galatík
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - D. Kolar
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - S. Vybiral
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - P. Alánová
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - J. Novotný
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - F. Kolar
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - O. Novakova
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - J. M. Zurmanova
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
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Du X, Zhao W, Nguyen M, Lu Q, Kiriazis H. β-Adrenoceptor activation affects galectin-3 as a biomarker and therapeutic target in heart disease. Br J Pharmacol 2019; 176:2449-2464. [PMID: 30756388 PMCID: PMC6592856 DOI: 10.1111/bph.14620] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/11/2018] [Accepted: 01/29/2019] [Indexed: 12/12/2022] Open
Abstract
Myocardial fibrosis is a key histopathological component that drives the progression of heart disease leading to heart failure and constitutes a therapeutic target. Recent preclinical and clinical studies have implicated galectin-3 (Gal-3) as a pro-fibrotic molecule and a biomarker of heart disease and fibrosis. However, our knowledge is poor on the mechanism(s) that determine the blood level or regulate cardiac expression of Gal-3. Recent studies have demonstrated that enhanced β-adrenoceptor activity is a determinant of both circulating concentration and cardiac expression of Gal-3. Pharmacological or transgenic activation of β-adrenoceptors leads to increased blood levels of Gal-3 and up-regulated cardiac Gal-3 expression, effect that can be reversed with the use of β-adrenoceptor antagonists. Conversely, Gal-3 gene deletion confers protection against isoprenaline-induced cardiotoxicity and fibrogenesis. At the transcription level, β-adrenoceptor stimulation activates cardiac mammalian sterile-20-like kinase 1, a pivotal kinase of the Hippo signalling pathway, which is associated with Gal-3 up-regulation. Recent studies have suggested a role for the β-adrenoceptor-Hippo signalling pathway in the regulation of cardiac Gal-3 expression thereby contributing to the onset and progression of heart disease. This implies a therapeutic potential of the suppression of Gal-3 expression. In this review, we discuss the effects of β-adrenoceptor activity on Gal-3 as a biomarker and causative mediator in the setting of heart disease and point out pivotal knowledge gaps. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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Affiliation(s)
- Xiao‐Jun Du
- Experimental Cardiology LaboratoryBaker Heart and Diabetes InstituteMelbourneVICAustralia
- Department of Physiology and Pathophysiology, School of Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
| | - Wei‐Bo Zhao
- Experimental Cardiology LaboratoryBaker Heart and Diabetes InstituteMelbourneVICAustralia
| | - My‐Nhan Nguyen
- Experimental Cardiology LaboratoryBaker Heart and Diabetes InstituteMelbourneVICAustralia
| | - Qun Lu
- Experimental Cardiology LaboratoryBaker Heart and Diabetes InstituteMelbourneVICAustralia
- Department of Cardiovascular Medicine, First HospitalXi'an Jiaotong University Health Science CenterXi'anChina
| | - Helen Kiriazis
- Experimental Cardiology LaboratoryBaker Heart and Diabetes InstituteMelbourneVICAustralia
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Abstract
Advances in the treatment of heart failure with reduced ejection fraction due to systolic dysfunction are engaging an ever-expanding compendium of molecular signaling targets. Well established approaches modifying hemodynamics and cell biology by neurohumoral receptor blockade are evolving, exploring the role and impact of modulating intracellular signaling pathways with more direct myocardial effects. Even well-tread avenues are being reconsidered with new insights into the signaling engaged and thus opportunity to treat underlying myocardial disease. This review explores therapies that have proven successful, those that have not, those that are moving into the clinic but whose utility remains to be confirmed, and those that remain in the experimental realm. The emphasis is on signaling pathways that are tractable for therapeutic manipulation. Of the approaches yet to be tested in humans, we chose those with a well-established experimental history, where clinical translation may be around the corner. The breadth of opportunities bodes well for the next generation of heart failure therapeutics.
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Affiliation(s)
| | | | - David A. Kass
- Division of Cardiology, Department of Medicine
- Department of Pharmacology and Molecular Sciences, The Johns Hopkins University, Baltimore Maryland, 21205
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Sogunmez N, Akten ED. Intrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human β 2-Adrenergic Receptor. J Phys Chem B 2019; 123:3630-3642. [PMID: 30946584 DOI: 10.1021/acs.jpcb.9b01202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The alternative inactive state of the human β2-adrenergic receptor originally exposed in molecular dynamics simulations was investigated using various analysis tools to evaluate causality between correlated residue-pair fluctuations and suggest allosteric communication pathways. A major conformational shift observed in the third intracellular loop (ICL3) displayed a novel inactive state, featuring an inaccessible G protein binding site blocked by ICL3 and an expanded orthosteric ligand binding site. Residue-based mean-square fluctuation and stiffness calculations revealed a significant mobility decrease in ICL3, which induced a mobility increase in the remaining loop regions. This indicates conformational entropy loss in one mobile region being compensated by residual intermolecular motions in other mobile regions. Moreover, the extent of significantly correlated motions decreased, and correlations that once existed between transmembrane helices shifted toward regions with increased mobility. Conditional time-delayed cross-correlation analysis identified distinct driver-follower relationship profiles. Prior to its packing, freely moving ICL3 was markedly driven by transmembrane helix-8 whereas once packed, ICL3 controlled future fluctuations of nearby helices. Moreover, two transmembrane helices, (H5 and H6), started to control future fluctuations of a remote site, the extracellular loop, ECL2. This clearly suggests that allosteric coupling between extra- and intracellular parts intensified, in agreement with the receptor's well recognized feature, which is the inverse proportionality between activity and the degree of coupling.
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Jevjdovic T, Dakic T, Kopanja S, Lakic I, Vujovic P, Jasnic N, Djordjevic J. Sex-Related Effects of Prenatal Stress on Region-Specific Expression of Monoamine Oxidase A and β Adrenergic Receptors in Rat Hearts. Arq Bras Cardiol 2018; 112:67-75. [PMID: 30569948 PMCID: PMC6317614 DOI: 10.5935/abc.20190001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 07/23/2018] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Prenatal stress may increase risk of developing cardiovascular disorders in adulthood. The cardiotoxic effects of catecholamines are mediated via prolonged adrenergic receptor stimulation and increased oxidative stress upon their degradation by monoamine oxidase A (MAO-A). OBJECTIVES We investigated long-term effects of prenatal stress on β (1, 2, 3) adrenergic receptors and MAO-A gene expression in the hearts of adult rat offspring. METHODS Pregnant rats were exposed to unpredictable mild stress during the third week of gestation. RNA was isolated from left ventricular apex and base of adult offspring. Quantitative PCR was used to measure gene expression in collected ventricular tissue samples. The level of significance was set to p < 0.05. RESULTS β3 adrenergic receptor mRNA was undetectable in rat left ventricle. β1 adrenergic receptor was the predominantly expressed subtype at the apical and basal left ventricular myocardium in the control females. Male offspring from unstressed mothers displayed higher apical cardiac β1 than β2 adrenergic receptor mRNA levels. However, β1 and β2 adrenergic receptor mRNAs were similarly expressed at the ventricular basal myocardium in males. Unlike males, prenatally stressed females exhibited decreased β1 adrenergic receptor mRNA expression at the apical myocardium. Prenatal stress did not affect cardiac MAO-A gene expression. CONCLUSIONS Collectively, our results show that prenatal stress may have exerted region- and sex-specific β1 and β2 adrenergic receptor expression patterns within the left ventricle.
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Affiliation(s)
- Tanja Jevjdovic
- Faculty of Biology - University of Belgrade, Belgrado - Sérvia
| | - Tamara Dakic
- Faculty of Biology - University of Belgrade, Belgrado - Sérvia
| | - Sonja Kopanja
- Department of Pediatrics and Adolescent Medicine - Medical University of Vienna, Viena - Áustria
| | - Iva Lakic
- Faculty of Biology - University of Belgrade, Belgrado - Sérvia
| | - Predrag Vujovic
- Faculty of Biology - University of Belgrade, Belgrado - Sérvia
| | - Nebojsa Jasnic
- Faculty of Biology - University of Belgrade, Belgrado - Sérvia
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Frank DU, Sutcliffe MD, Saucerman JJ. Network-based predictions of in vivo cardiac hypertrophy. J Mol Cell Cardiol 2018; 121:180-189. [PMID: 30030017 DOI: 10.1016/j.yjmcc.2018.07.243] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 07/12/2018] [Accepted: 07/16/2018] [Indexed: 12/13/2022]
Abstract
Cardiac hypertrophy is a common response of cardiac myocytes to stress and a predictor of heart failure. While in vitro cell culture studies have identified numerous molecular mechanisms driving hypertrophy, it is unclear to what extent these mechanisms can be integrated into a consistent framework predictive of in vivo phenotypes. To address this question, we investigate the degree to which an in vitro-based, manually curated computational model of the hypertrophy signaling network is able to predict in vivo hypertrophy of 52 cardiac-specific transgenic mice. After minor revisions motivated by in vivo literature, the model concordantly predicts the qualitative responses of 78% of output species and 69% of signaling intermediates within the network model. Analysis of four double-transgenic mouse models reveals that the computational model robustly predicts hypertrophic responses in mice subjected to multiple, simultaneous perturbations. Thus the model provides a framework with which to mechanistically integrate data from multiple laboratories and experimental systems to predict molecular regulation of cardiac hypertrophy.
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Affiliation(s)
- Deborah U Frank
- Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville 22908, VA, United States; Department of Pediatrics, University of Virginia, HSC Box 800386, Charlottesville 22908-0386, VA, United States.
| | - Matthew D Sutcliffe
- Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville 22908, VA, United States; Department of Pediatrics, University of Virginia, HSC Box 800386, Charlottesville 22908-0386, VA, United States.
| | - Jeffrey J Saucerman
- Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville 22908, VA, United States.
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31
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Nguyen MN, Su Y, Kiriazis H, Yang Y, Gao XM, McMullen JR, Dart AM, Du XJ. Upregulated galectin-3 is not a critical disease mediator of cardiomyopathy induced by β2-adrenoceptor overexpression. Am J Physiol Heart Circ Physiol 2018; 314:H1169-H1178. [DOI: 10.1152/ajpheart.00337.2017] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Preclinical studies have demonstrated that anti-galectin-3 (Gal-3) interventions are effective in attenuating cardiac remodeling, fibrosis, and dysfunction. We determined, in a transgenic (TG) mouse model of fibrotic cardiomyopathy, whether Gal-3 expression was elevated and whether Gal-3 played a critical role in disease development. We studied mice with fibrotic cardiomyopathy attributable to cardiac overexpression of human β2-adrenoceptors (β2-TG). Cardiac expression levels of Gal-3 and fibrotic or inflammatory genes were determined. The effect of Gal-3 inhibition in β2-TG mice was studied by treatment with Gal-3 inhibitors ( N-acetyllactosamine and modified citrus pectin) or by deletion of Gal-3 through crossing β2-TG and Gal-3 knockout mice. Changes in cardiomyopathy phenotypes were assessed by echocardiography and biochemical assays. In β2-TG mice at 3, 6, and 9 mo of age, upregulation of Gal-3 expression was observed at mRNA (~6- to 15-fold) and protein (~4- to 8-fold) levels. Treatment of β2-TG mice with N-acetyllactosamine (3 wk) or modified citrus pectin (3 mo) did not reverse cardiac fibrosis, inflammation, and cardiomyopathy. Similarly, Gal-3 gene deletion in β2-TG mice aged 3 and 9 mo did not rescue the cardiomyopathy phenotype. In conclusion, the β2-TG model of cardiomyopathy showed a robust upregulation of Gal-3 that correlated with disease severity, but Gal-3 inhibitors or Gal-3 gene deletion had no effect in halting myocardial fibrosis, remodeling, and dysfunction. Gal-3 may not be critical for cardiac fibrogenesis and remodeling in this cardiomyopathy model. NEW & NOTEWORTHY We showed a robust upregulation of cardiac galectin-3 (Gal-3) expression in a mouse model of cardiomyopathy attributable to cardiomyocyte-restricted transgenic activation of β2-adrenoceptors. However, pharmacological and genetic inhibition of Gal-3 did not confer benefit in this model, implying that Gal-3 may not be a critical disease mediator of cardiac remodeling in this model.
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Affiliation(s)
- My-Nhan Nguyen
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Yidan Su
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Helen Kiriazis
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Yan Yang
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Alfred Heart Centre, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Xiao-Ming Gao
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Julie R. McMullen
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Anthony M. Dart
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Alfred Heart Centre, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Xiao-Jun Du
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, Melbourne, Victoria, Australia
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Abstract
The opioid receptor family, with associated endogenous ligands, has numerous roles throughout the body. Moreover, the delta opioid receptor (DORs) has various integrated roles within the physiological systems, including the cardiovascular system. While DORs are important modulators of cardiovascular autonomic balance, they are well-established contributors to cardioprotective mechanisms. Both endogenous and exogenous opioids acting upon DORs have roles in myocardial hibernation and protection against ischaemia-reperfusion (I-R) injury. Downstream signalling mechanisms governing protective responses alternate, depending on the timing and duration of DOR activation. The following review describes models and mechanisms of DOR-mediated cardioprotection, the impact of co-morbidities and challenges for clinical translation.
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Affiliation(s)
- Louise See Hoe
- Menzies Health Institute Queensland, Griffith University, Southport, QLD, 4222, Australia
- Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Chermside, QLD, Australia
| | - Hemal H Patel
- VA San Diego Healthcare System, San Diego, CA, USA
- Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA
| | - Jason N Peart
- Menzies Health Institute Queensland, Griffith University, Southport, QLD, 4222, Australia.
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Rozier K, Bondarenko VE. Mathematical modeling physiological effects of the overexpression of β 2-adrenoceptors in mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 2017; 314:H643-H658. [PMID: 29101164 DOI: 10.1152/ajpheart.00160.2017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Transgenic (TG) mice overexpressing β2-adrenergic receptors (β2-ARs) demonstrate enhanced myocardial function, which manifests in increased basal adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo. To gain insights into the mechanisms of these effects, we developed a comprehensive mathematical model of the mouse ventricular myocyte overexpressing β2-ARs. We found that most of the β2-ARs are active in control conditions in TG mice. The simulations describe the dynamics of major signaling molecules in different subcellular compartments, increased basal adenylyl cyclase activity, modifications of action potential shape and duration, and the effects on L-type Ca2+ current and intracellular Ca2+ concentration ([Ca2+]i) transients upon stimulation of β2-ARs in control, after the application of pertussis toxin, upon stimulation with a specific β2-AR agonist zinterol, and upon stimulation with zinterol in the presence of pertussis toxin. The model also describes the effects of the β2-AR inverse agonist ICI-118,551 on adenylyl cyclase activity, action potential, and [Ca2+]i transients. The simulation results were compared with experimental data obtained in ventricular myocytes from TG mice overexpressing β2-ARs and with simulation data on wild-type mice. In conclusion, a new comprehensive mathematical model was developed that describes multiple experimental data on TG mice overexpressing β2-ARs and can be used to test numerous hypotheses. As an example, using the developed model, we proved the hypothesis of the major contribution of L-type Ca2+ current to the changes in the action potential and [Ca2+]i transient upon stimulation of β2-ARs with zinterol. NEW & NOTEWORTHY We developed a new mathematical model for transgenic mouse ventricular myocytes overexpressing β2-adrenoceptors that describes the experimental findings in transgenic mice. The model reveals mechanisms of the differential effects of stimulation of β2-adrenoceptors in wild-type and transgenic mice overexpressing β2-adrenoceptors.
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Affiliation(s)
- Kelvin Rozier
- Department of Mathematics and Statistics, Georgia State University , Atlanta, Georgia
| | - Vladimir E Bondarenko
- Department of Mathematics and Statistics, Georgia State University , Atlanta, Georgia.,Neuroscience Institute, Georgia State University , Atlanta, Georgia
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Lorenz K, Rosner MR, Brand T, Schmitt JP. Raf kinase inhibitor protein: lessons of a better way for β-adrenergic receptor activation in the heart. J Physiol 2017; 595:4073-4087. [PMID: 28444807 PMCID: PMC5471367 DOI: 10.1113/jp274064] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 02/27/2017] [Indexed: 12/13/2022] Open
Abstract
Stimulation of β-adrenergic receptors (βARs) provides the most efficient physiological mechanism to enhance contraction and relaxation of the heart. Activation of βARs allows rapid enhancement of myocardial function in order to fuel the muscles for running and fighting in a fight-or-flight response. Likewise, βARs become activated during cardiovascular disease in an attempt to counteract the restrictions of cardiac output. However, long-term stimulation of βARs increases the likelihood of cardiac arrhythmias, adverse ventricular remodelling, decline of cardiac performance and premature death, thereby limiting the use of βAR agonists in the treatment of heart failure. Recently the endogenous Raf kinase inhibitor protein (RKIP) was found to activate βAR signalling of the heart without adverse effects. This review will summarize the current knowledge on RKIP-driven compared to receptor-mediated signalling in cardiomyocytes. Emphasis is given to the differential effects of RKIP on β1 - and β2 -ARs and their downstream targets, the regulation of myocyte calcium cycling and myofilament activity.
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Affiliation(s)
- Kristina Lorenz
- Comprehensive Heart Failure CenterUniversity of WürzburgVersbacher Straße 997078WürzburgGermany
- West German Heart and Vascular Center EssenUniversity Hospital EssenHufelandstraße 5545147EssenGermany
- Leibniz‐Institut für Analytische Wissenschaften – ISAS – e.V.Bunsen‐Kirchhoff‐Straße 1144139DortmundGermany
- Institute of Pharmacology and ToxicologyUniversity of WürzburgVersbacher Straße 997078WürzburgGermany
| | - Marsha Rich Rosner
- Ben May Department for Cancer ResearchUniversity of ChicagoChicagoIL 60637USA
| | - Theresa Brand
- Leibniz‐Institut für Analytische Wissenschaften – ISAS – e.V.Bunsen‐Kirchhoff‐Straße 1144139DortmundGermany
- Institute of Pharmacology and ToxicologyUniversity of WürzburgVersbacher Straße 997078WürzburgGermany
| | - Joachim P Schmitt
- Institute of Pharmacology and Clinical PharmacologyDüsseldorf University HospitalUniverstitätsstraße 140225DüsseldorfGermany
- Cardiovascular Research Institute Düsseldorf (CARID)Heinrich‐Heine‐UniversityUniverstitätsstraße 140225DüsseldorfGermany
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Tae HJ, Petrashevskaya N, Kim IH, Park JH, Lee JC, Won MH, Kim YH, Ahn JH, Park J, Choi SY, Jeon YH. G protein, phosphorylated-GATA4 and VEGF expression in the hearts of transgenic mice overexpressing β1- and β2-adrenergic receptors. Mol Med Rep 2017; 15:4049-4054. [PMID: 28487987 PMCID: PMC5436146 DOI: 10.3892/mmr.2017.6526] [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: 04/28/2016] [Accepted: 02/22/2017] [Indexed: 11/27/2022] Open
Abstract
β1- and β2-adrenergic receptors (ARs) regulate cardiac contractility, calcium handling and protein phosphorylation. The present study aimed to examine the expression levels of vascular endothelial growth factor A (VEGF-A) and several G proteins, and the phosphorylation of transcription factor GATA binding protein 4 (GATA4), by western blot analysis, using isolated hearts from 6 month-old transgenic (TG) mice that overexpress β1AR or β2AR. Cardiac contractility/relaxation and heart rate was increased in both β1AR TG and β2AR TG mouse hearts compared with wild type; however, no significant differences were observed between the β1- and β2AR TG mouse hearts. Protein expression levels of inhibitory guanine nucleotide-binding protein (Gi) 2, Gi3 and G-protein-coupled receptor kinase 2 were upregulated in both TG mice, although the upregulation of Gi2 was more prominent in the β2AR TG mice. VEGF-A expression levels were also increased in both TG mice, and were highest in the β1AR TG mice. In addition, the levels of phosphorylated-GATA4 expression were increased in β1- and β2AR TG mice. In conclusion, the present study demonstrated that cardiac contractility/relaxation and heart rate is increased in β1AR TG and β2AR TG mice, and indicated that this increase may be related to the overexpression of G proteins and G-protein-associated proteins.
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Affiliation(s)
- Hyun-Jin Tae
- Bio‑Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeollabuk 54596, Republic of Korea
| | - Natalia Petrashevskaya
- Cardiopulmonary Genomics Program, Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - In Hye Kim
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Joon Ha Park
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Jae-Chul Lee
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Moo-Ho Won
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Yang Hee Kim
- Department of Surgery, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24289, Republic of Korea
| | - Ji Hyeon Ahn
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea
| | - Jinseu Park
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea
| | - Soo Young Choi
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea
| | - Yong Hwan Jeon
- Department of Radiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24289, Republic of Korea
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Xing F, Chen J, Zhao B, Jiang J, Tang A, Chen Y. Real role of β-blockers in regression of left ventricular mass in hypertension patients: Bayesian network meta-analysis. Medicine (Baltimore) 2017; 96:e6290. [PMID: 28272254 PMCID: PMC5348202 DOI: 10.1097/md.0000000000006290] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Left ventricular hypertrophy (LVH) is commonly present in patients with hypertension (HT). According to the expert consensus document from American, angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARBs) were recommended as 1st-line therapeutic drugs. However, none noticed the different efficacy between fat-soluble and selective β1-receptor blockers (FS-β-B) and other β-blockers on regression of LVH before. The aim of this analysis was to compare the efficacy of FS-β-B with the other 4 different classes of antihypertensive drugs (ACEI, ARBs, calcium channel blockers [CCBs], and diuretics) on regression of LVH. METHODS Relative trials were identified in the PubMed, Web of Science, OVID EBM Reviews and Cochrane databases, and the relevant papers were examined. We performed both traditional and Bayesian meta-analysis of randomized controlled trials (RCTs) about the regression of LVH. Sensitivity analysis and regression analysis were performed to explore possible sources of heterogeneity. Inconsistency analysis was performed to check whether the analysis of the trials in the network was indeed consistent. RESULTS A total of 41 RCTs involving 2566 patients with HT and LVH were included in this analysis. Bayesian network meta-analysis indicated no statistically significant differences between these groups: FS-β-B and ACEI (MD, -7.09; 95% CI, -14.99, 1.27); FS-β-B and ARB (MD, -2.66; 95% Cl, -12.02, 6.31). Although FS-β-B showed greater efficacy when compared with diuretic (MD, 13.04; 95% CI, 3.38, 22.59) or CCB (MD, 10.90; 95% CI, 1.98, 19.49). The probabilities of being among the most efficacious treatments were: FS-β-B (72%), ARB (27%), ACEI (0.01%), CCB (0.00%), and diuretic (0.00%). CONCLUSION Evidence from our analysis reveals that FS-β-B have potential to become 1st-line therapeutic drugs in HT and LVH patients. However, the real efficacy of FS-β-B on regression of LVH should be confirmed by further large, high quality trials considering the limitation of the study number.
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Affiliation(s)
- FuWei Xing
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University
| | - Jialin Chen
- Zhongshan School of Medicine, Sun Yat-sen University
| | - BinLiang Zhao
- Nuclear Medicine Department, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Jingzhou Jiang
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University
| | - Anli Tang
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University
| | - Yili Chen
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University
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Lin TY, Chen CY, Huang YB. Evaluating the effectiveness of different beta-adrenoceptor blockers in heart failure patients. Int J Cardiol 2016; 230:378-383. [PMID: 28041715 DOI: 10.1016/j.ijcard.2016.12.098] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/13/2016] [Accepted: 12/17/2016] [Indexed: 12/28/2022]
Abstract
BACKGROUND According to guidelines and pivotal trials, β-blockers are associated with better survival in patients with heart failure (HF). However, the superiority of any β-blockers is still unclear. METHODS This retrospective cohort study was conducted using the National Health Insurance Research Database in Taiwan to evaluate the effectiveness of β-blockers and compare the clinical outcomes of different β-blockers in patients with HF. We enrolled patients diagnosed with HF between 2005 and 2012. We then stratified the β-blockers according to the starting dose: lower in group 1 and higher in group 2. A time-dependent Cox proportional hazards regression model was applied to evaluate the effectiveness of the β-blockers. RESULTS A total of 14,875 patients with HF were identified during the study period. After propensity-score matching, 5688 patients were included in both the β-blocker user and nonuser groups. We found that group 2 carvedilol and group 2 bisoprolol significantly reduced the risk of death and hospitalization for HF, whereas metoprolol did not. Compared with group 2 carvedilol, survival was not significantly different for group 2 bisoprolol (adjusted hazard ratio=1.18, 95% confidence interval=0.88-1.58). CONCLUSION From results, carvedilol and bisoprolol were associated with better outcomes, with no difference between these two β-blockers in patients with HF in Taiwan.
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Affiliation(s)
- Tien-Yu Lin
- School of Pharmacy, Master Program in Clinical Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Yu Chen
- School of Pharmacy, Master Program in Clinical Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Yaw-Bin Huang
- School of Pharmacy, Master Program in Clinical Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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Abstract
Hundreds of different mutations in genes encoding a few dozen sarcomeric proteins cause two reciprocal human disease phenotypes, hypertrophic or dilated cardiomyopathy. How molecular dysfunction evokes different patterns of cardiac remodeling is unclear. Davis et al. describe a biophysical metric of cardiomyocyte function, the force-time integral, which predicts disease phenotype.
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Affiliation(s)
- Gerald W Dorn
- Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Ohnuki Y, Umeki D, Mototani Y, Shiozawa K, Nariyama M, Ito A, Kawamura N, Yagisawa Y, Jin H, Cai W, Suita K, Saeki Y, Fujita T, Ishikawa Y, Okumura S. Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol. Physiol Rep 2016; 4:4/10/e12791. [PMID: 27207782 PMCID: PMC4886163 DOI: 10.14814/phy2.12791] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 04/08/2016] [Indexed: 02/04/2023] Open
Abstract
Clenbuterol (CB), a selective β2-adrenergic receptor (AR) agonist, induces muscle hypertrophy and counteracts muscle atrophy. However, it is paradoxically less effective in slow-twitch muscle than in fast-twitch muscle, though slow-twitch muscle has a greater density of β-AR We recently demonstrated that Epac1 (exchange protein activated by cyclic AMP [cAMP]1) plays a pivotal role in β2-AR-mediated masseter muscle hypertrophy through activation of the Akt and calmodulin kinase II (CaMKII)/histone deacetylase 4 (HDAC4) signaling pathways. Here, we investigated the role of Epac1 in the differential hypertrophic effect of CB using tibialis anterior muscle (TA; typical fast-twitch muscle) and soleus muscle (SOL; typical slow-twitch muscle) of wild-type (WT) and Epac1-null mice (Epac1KO). The TA mass to tibial length (TL) ratio was similar in WT and Epac1KO at baseline and was significantly increased after CB infusion in WT, but not in Epac1KO The SOL mass to TL ratio was also similar in WT and Epac1KO at baseline, but CB-induced hypertrophy was suppressed in both mice. In order to understand the mechanism involved, we measured the protein expression levels of β-AR signaling-related molecules, and found that phosphodiesterase 4 (PDE4) expression was 12-fold greater in SOL than in TA These results are consistent with the idea that increased PDE4-mediated cAMP hydrolysis occurs in SOL compared to TA, resulting in a reduced cAMP concentration that is insufficient to activate Epac1 and its downstream Akt and CaMKII/HDAC4 hypertrophic signaling pathways in SOL of WT This scenario can account for the differential effects of CB on fast- and slow-twitch muscles.
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Affiliation(s)
- Yoshiki Ohnuki
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Daisuke Umeki
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Yasumasa Mototani
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Kouichi Shiozawa
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Megumi Nariyama
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Pediatric Dentistry, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Aiko Ito
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Naoya Kawamura
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Periodontology, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Yuka Yagisawa
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Huiling Jin
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Wenqian Cai
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kenji Suita
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasutake Saeki
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan
| | - Takayuki Fujita
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yoshihiro Ishikawa
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Satoshi Okumura
- Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Kim KE, Tae HJ, Natalia P, Lee JC, Ahn JH, Park JH, Kim IH, Ohk TG, Park CW, Cho JH, Won MH. Cardiac physiologic regulation of sub-type specific adrenergic receptors in transgenic mice overexpressing β 1- and β 2-adrenergic receptors. Clin Exp Emerg Med 2016; 3:175-180. [PMID: 27752636 PMCID: PMC5065340 DOI: 10.15441/ceem.16.141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 04/29/2016] [Accepted: 05/10/2016] [Indexed: 01/28/2023] Open
Abstract
Objective Combination of β1-adrenergic receptor (AR) blockade and β2-AR activation might be a potential novel therapy for treating heart failure. However, use of β-AR agonists and/or antagonists in the clinical setting is controversial because of the lack of information on cardiac inotropic or chronotropic regulation by AR signaling. Methods In this study, we performed hemodynamic evaluation by examining force frequency response (FFR), Frank-Starling relationship, and response to a non-selective β-AR agonist (isoproterenol) in hearts isolated from 6-month-old transgenic (TG) mice overexpressing β1- and β2-ARs (β1- and β2-AR TG mice, respectively). Results Cardiac physiologic consequences of β1- and β2-AR overexpression resulted in similar maximal response to isoproterenol and faster temporary decline of positive inotropic response in β2-AR TG mice. β1-AR TG mice showed a pronounced negative limb of FFR, whereas β2-AR TG mice showed high stimulation frequencies with low contractile depression during FFR. In contrast, Frank-Starling relationship was equally enhanced in both β1- and β2-AR TG mice. Conclusion Hemodynamic evaluation performed in the present showed a difference in β1- and β2-AR signaling, which may be due to the difference in the desensitization of β1- and β2-ARs.
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Affiliation(s)
- Ka Eul Kim
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Korea
| | - Hyun-Jin Tae
- Department of Emergency Medicine, Kangwon National University School of Medicine, Chuncheon, Korea; Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Korea
| | - Petrashevskaya Natalia
- CardioPulmonary Genomics Program, Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jae-Chul Lee
- Department of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Ji Hyeon Ahn
- Department of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Joon Ha Park
- Department of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Korea
| | - In Hye Kim
- Department of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Taek Geun Ohk
- Department of Emergency Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Chan Woo Park
- Department of Emergency Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Jun Hwi Cho
- Department of Emergency Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Moo-Ho Won
- Department of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Korea
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Jaiswal A, Nguyen VQ, Le Jemtel TH, Ferdinand KC. Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure. World J Cardiol 2016; 8:401-412. [PMID: 27468333 PMCID: PMC4958691 DOI: 10.4330/wjc.v8.i7.401] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 04/28/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
In advanced heart failure (HF), chronic inotropic therapy with intravenous milrinone, a phosphodiesterase III inhibitor, is used as a bridge to advanced management that includes transplantation, ventricular assist device implantation, or palliation. This is especially true when repeated attempts to wean off inotropic support result in symptomatic hypotension, worsened symptoms, and/or progressive organ dysfunction. Unfortunately, patients in this clinical predicament are considered hemodynamically labile and may escape the benefits of guideline-directed HF therapy. In this scenario, chronic milrinone infusion may be beneficial as a bridge to introduction of evidence based HF therapy. However, this strategy is not well studied, and in general, chronic inotropic infusion is discouraged due to potential cardiotoxicity that accelerates disease progression and proarrhythmic effects that increase sudden death. Alternatively, chronic inotropic support with milrinone infusion is a unique opportunity in advanced HF. This review discusses evidence that long-term intravenous milrinone support may allow introduction of beta blocker (BB) therapy. When used together, milrinone does not attenuate the clinical benefits of BB therapy while BB mitigates cardiotoxic effects of milrinone. In addition, BB therapy decreases the risk of adverse arrhythmias associated with milrinone. We propose that advanced HF patients who are intolerant to BB therapy may benefit from a trial of intravenous milrinone as a bridge to BB initiation. The discussed clinical scenarios demonstrate that concomitant treatment with milrinone infusion and BB therapy does not adversely impact standard HF therapy and may improve left ventricular function and morbidity associated with advanced HF.
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Abstract
Aging is characterized by the progressive accumulation of degenerative changes, culminating in impaired function and increased probability of death. It is the major risk factor for many human pathologies - including cancer, type 2 diabetes, and cardiovascular and neurodegenerative diseases - and consequently exerts an enormous social and economic toll. The major goal of aging research is to develop interventions that can delay the onset of multiple age-related diseases and prolong healthy lifespan (healthspan). The observation that enhanced longevity and health can be achieved in model organisms by dietary restriction or simple genetic manipulations has prompted the hunt for chemical compounds that can increase lifespan. Most of the pathways that modulate the rate of aging in mammals have homologs in yeast, flies, and worms, suggesting that initial screening to identify such pharmacological interventions may be possible using invertebrate models. In recent years, several compounds have been identified that can extend lifespan in invertebrates, and even in rodents. Here, we summarize the strategies employed, and the progress made, in identifying compounds capable of extending lifespan in organisms ranging from invertebrates to mice and discuss the formidable challenges in translating this work to human therapies.
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Affiliation(s)
- Surinder Kumar
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - David B Lombard
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA; Institute of Gerontology, University of Michigan, Ann Arbor, MI, 48109, USA
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Lee HY, Chung WJ, Jeon HK, Seo HS, Choi DJ, Jeon ES, Kim JJ, Shin JH, Kang SM, Lim SC, Baek SH. Impact of the β-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between β adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study. Korean J Intern Med 2016; 31:277-87. [PMID: 26879662 PMCID: PMC4773723 DOI: 10.3904/kjim.2015.043] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Revised: 08/17/2015] [Accepted: 12/11/2015] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS We evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF). METHODS One hundred patients with stable CHF (left ventricular ejection fraction [LVEF] < 45%) were enrolled. Enrolled patients started 1.25 mg bisoprolol treatment once daily, then up-titrated to the maximally tolerable dose, at which they were treated for 1 year. RESULTS Genotypic analysis was carried out, but the results were blinded to the investigators throughout the study period. At position 389 of the β-1 adrenergic receptor gene (ADRB1), the observed minor Gly allele frequency (Gly389Arg + Gly389Gly) was 0.21, and no deviation from Hardy-Weinberg equilibrium was observed in the genotypic distribution of Arg389Gly (p = 0.75). Heart rate was reduced from 80.8 ± 14.3 to 70.0 ± 15.0 beats per minute (p < 0.0001). There was no significant difference in final heart rate across genotypes. However, the Arg389Arg genotype group required significantly more bisoprolol compared to the Gly389X (Gly389Arg + Gly389Gly) group (5.26 ± 2.62 mg vs. 3.96 ± 2.05 mg, p = 0.022). There were no significant differences in LVEF changes or remodeling between two groups. Also, changes in exercise capacity and brain natriuretic peptide level were not significant. However, interestingly, there was a two-fold higher rate of readmission (21.2% vs. 10.0%, p = 0.162) and one CHF-related death in the Arg389Arg group. CONCLUSIONS The ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring β-blocker therapy according to genotype.
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Affiliation(s)
- Hae-Young Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Wook-Jin Chung
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Hui-Kyung Jeon
- Department of Internal Medicine, College of Medicine, Uijeongbu St. Mary’s Hospital, The Catholic University of Korea, Uijeongbu, Korea
| | - Hong-Seog Seo
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea
| | - Dong-Ju Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Eun-Seok Jeon
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Joong Kim
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joon Han Shin
- Department of Internal Medicine, Ajou University Hospital, Suwon, Korea
| | - Seok-Min Kang
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Cil Lim
- Department of Clinical Pharmacy, College of Pharmacy, The Catholic University of Korea, Seoul, Korea
| | - Sang-Hong Baek
- Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
- Correspondence to Sang Hong Baek, M.D.Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: +82-2-2258-6030 Fax: +82-2-591-1506 E-mail:
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44
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Abstract
Beta-blockers are the cornerstone treatment for congestive heart failure (HF). Current HF guidelines commonly recommend β-blockers for the treatment of HF with reduced left ventricular ejection fraction (LVEF). The effect of β-blockers, however, is less clear for HF patients with preserved LVEF, unstable severe acute HF, or right ventricular failure. This review summarizes the effect of β-blockers in various clinical situations and suggests a strategy for optimal use. (Circ J 2016; 80: 565-571).
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Affiliation(s)
- Hae-Young Lee
- Internal Medicine, Seoul National University Hospital
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45
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Dolatshad NF, Hellen N, Jabbour RJ, Harding SE, Földes G. G-protein Coupled Receptor Signaling in Pluripotent Stem Cell-derived Cardiovascular Cells: Implications for Disease Modeling. Front Cell Dev Biol 2015; 3:76. [PMID: 26697426 PMCID: PMC4673467 DOI: 10.3389/fcell.2015.00076] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Accepted: 11/09/2015] [Indexed: 12/13/2022] Open
Abstract
Human pluripotent stem cell derivatives show promise as an in vitro platform to study a range of human cardiovascular diseases. A better understanding of the biology of stem cells and their cardiovascular derivatives will help to understand the strengths and limitations of this new model system. G-protein coupled receptors (GPCRs) are key regulators of stem cell maintenance and differentiation and have an important role in cardiovascular cell signaling. In this review, we will therefore describe the state of knowledge concerning the regulatory role of GPCRs in both the generation and function of pluripotent stem cell derived-cardiomyocytes, -endothelial, and -vascular smooth muscle cells. We will consider how far the in vitro disease models recapitulate authentic GPCR signaling and provide a useful basis for discovery of disease mechanisms or design of therapeutic strategies.
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Affiliation(s)
- Nazanin F Dolatshad
- Myocardial Function, National Heart and Lung Institute, Imperial College London London, UK
| | - Nicola Hellen
- Myocardial Function, National Heart and Lung Institute, Imperial College London London, UK
| | - Richard J Jabbour
- Myocardial Function, National Heart and Lung Institute, Imperial College London London, UK
| | - Sian E Harding
- Myocardial Function, National Heart and Lung Institute, Imperial College London London, UK
| | - Gabor Földes
- Myocardial Function, National Heart and Lung Institute, Imperial College London London, UK ; The Heart and Vascular Center of Semmelweis University, Semmelweis University Budapest, Hungary
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46
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Schmid E, Neef S, Berlin C, Tomasovic A, Kahlert K, Nordbeck P, Deiss K, Denzinger S, Herrmann S, Wettwer E, Weidendorfer M, Becker D, Schäfer F, Wagner N, Ergün S, Schmitt JP, Katus HA, Weidemann F, Ravens U, Maack C, Hein L, Ertl G, Müller OJ, Maier LS, Lohse MJ, Lorenz K. Cardiac RKIP induces a beneficial β-adrenoceptor-dependent positive inotropy. Nat Med 2015; 21:1298-306. [PMID: 26479924 DOI: 10.1038/nm.3972] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/12/2015] [Indexed: 01/08/2023]
Abstract
In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β1-adrenoceptor (β1AR). This result is unexpected, as β1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.
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Affiliation(s)
- Evelyn Schmid
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Stefan Neef
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Christopher Berlin
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Angela Tomasovic
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Katrin Kahlert
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Peter Nordbeck
- Comprehensive Heart Failure Center, Würzburg, Germany.,Department of Internal Medicine I, University of Würzburg, Würzburg, Germany
| | - Katharina Deiss
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Sabrina Denzinger
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Sebastian Herrmann
- Comprehensive Heart Failure Center, Würzburg, Germany.,Department of Internal Medicine I, University of Würzburg, Würzburg, Germany
| | - Erich Wettwer
- Department of Pharmacology and Toxicology, Medical Faculty Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Markus Weidendorfer
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Daniel Becker
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Florian Schäfer
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Nicole Wagner
- Institute of Anatomy and Cell Biology, Würzburg, Germany
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, Würzburg, Germany
| | - Joachim P Schmitt
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Hugo A Katus
- Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.,German Centre for Cardiovascular Research, Heidelberg University Hospital, Heidelberg, Germany
| | - Frank Weidemann
- Comprehensive Heart Failure Center, Würzburg, Germany.,Department of Internal Medicine I, University of Würzburg, Würzburg, Germany
| | - Ursula Ravens
- Department of Pharmacology and Toxicology, Medical Faculty Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Christoph Maack
- Clinic for Internal Medicine III, Saarland University Hospital, Homburg, Germany
| | - Lutz Hein
- Institute of Experimental and Clinical Pharmacology and Toxicology, Freiburg, Germany.,Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany
| | - Georg Ertl
- Comprehensive Heart Failure Center, Würzburg, Germany.,Department of Internal Medicine I, University of Würzburg, Würzburg, Germany
| | - Oliver J Müller
- Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.,German Centre for Cardiovascular Research, Heidelberg University Hospital, Heidelberg, Germany
| | - Lars S Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Martin J Lohse
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.,Comprehensive Heart Failure Center, Würzburg, Germany
| | - Kristina Lorenz
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.,Comprehensive Heart Failure Center, Würzburg, Germany
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47
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Keller K, Maass M, Dizayee S, Leiss V, Annala S, Köth J, Seemann WK, Müller-Ehmsen J, Mohr K, Nürnberg B, Engelhardt S, Herzig S, Birnbaumer L, Matthes J. Lack of Gαi2 leads to dilative cardiomyopathy and increased mortality in β1-adrenoceptor overexpressing mice. Cardiovasc Res 2015; 108:348-56. [PMID: 26464333 DOI: 10.1093/cvr/cvv235] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 09/28/2015] [Indexed: 01/05/2023] Open
Abstract
AIMS Inhibitory G (Gi) proteins have been proposed to be cardioprotective. We investigated effects of Gαi2 knockout on cardiac function and survival in a murine heart failure model of cardiac β1-adrenoceptor overexpression. METHODS AND RESULTS β1-transgenic mice lacking Gαi2 (β1-tg/Gαi2 (-/-)) were compared with wild-type mice and littermates either overexpressing cardiac β1-adrenoceptors (β1-tg) or lacking Gαi2 (Gαi2 (-/-)). At 300 days, mortality of mice only lacking Gαi2 was already higher compared with wild-type or β1-tg, but similar to β1-tg/Gαi2 (-/-), mice. Beyond 300 days, mortality of β1-tg/Gαi2 (-/-) mice was enhanced compared with all other genotypes (mean survival time: 363 ± 21 days). At 300 days of age, echocardiography revealed similar cardiac function of wild-type, β1-tg, and Gαi2 (-/-) mice, but significant impairment for β1-tg/Gαi2 (-/-) mice (e.g. ejection fraction 14 ± 2 vs. 40 ± 4% in wild-type mice). Significantly increased ventricle-to-body weight ratio (0.71 ± 0.06 vs. 0.48 ± 0.02% in wild-type mice), left ventricular size (length 0.82 ± 0.04 vs. 0.66 ± 0.03 cm in wild types), and atrial natriuretic peptide and brain natriuretic peptide expression (mRNA: 2819 and 495% of wild-type mice, respectively) indicated hypertrophy. Gαi3 was significantly up-regulated in Gαi2 knockout mice (protein compared with wild type: 340 ± 90% in Gαi2 (-/-) and 394 ± 80% in β1-tg/Gαi2 (-/-), respectively). CONCLUSIONS Gαi2 deficiency combined with cardiac β1-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, β1-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking Gαi2. We propose an enhanced effect of increased β1-adrenergic drive by the lack of protection via Gαi2. Gαi3 up-regulation was not sufficient to compensate for Gαi2 deficiency, suggesting an isoform-specific or a concentration-dependent mechanism.
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Affiliation(s)
- Kirsten Keller
- Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany
| | - Martina Maass
- Department of Internal Medicine III, University Hospital of Cologne, Cologne, Germany
| | - Sara Dizayee
- Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany
| | - Veronika Leiss
- Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany
| | - Suvi Annala
- Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany
| | - Jessica Köth
- Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany
| | - Wiebke K Seemann
- Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany
| | | | - Klaus Mohr
- Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany
| | - Bernd Nürnberg
- Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technische Universität München, Munich, Germany
| | - Stefan Herzig
- Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany
| | - Lutz Birnbaumer
- Laboratory of Neurobiology, NIEHS, NIH (Department of Health and Human Services), Durham, USA
| | - Jan Matthes
- Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany
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48
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Kang S, Hong X, Ruan CW, Yu P, Yu SS, Chen M, Zhang DF, Fan HM, Liu ZM. Effects of GRK5 and ADRB1 polymorphisms influence on systolic heart failure. J Transl Med 2015; 13:44. [PMID: 25638254 PMCID: PMC4345005 DOI: 10.1186/s12967-015-0402-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 01/16/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND G-protein receptor kinase 5 (GRK5) Gln41 > Leu and β1-adrenergic receptor (ADRB1) Arg389 > Gly polymorphisms presented the different distribution of genotype frequencies between Caucasian American and African American, and produced the difference in β-blocker treatment effect among them with systolic heart failure (SHF). OBJECTIVE This study sought to identify the distributed characteristics of these variant genotypes in Chinese population, and influence of GRK5 and ADRB1 polymorphisms on SHF morbidity and β-blocker treatment effect in patients with SHF. METHODS This study was based on cross-sectional survey data. 1794 and 1718 subjects' ADRB1 and GRK5 gene sequencing (sanger method) data were achieved respectively. Blood samples collection, clinical laboratory detection, electrocardiogram and echocardiography examinations were performed. Medication usage was confirmed at in-hospital visits or the questionnaire by personal interview. RESULTS GRK5 Leu41Leu genotype was not found in our Chinese population. In non-SHF population, allele frequencies of GRK5 Gln41 and Leu41 were 2782 (0.992) and 22 (0.008) (Hardy-Weinberg equilibrium test χ(2) = 0.088, P = 0.767), and allele frequencies of ADRB1 Arg389 and Gly389 were 2127 (0.715) and 849 (0.285) (χ(2) = 0.272, P = 0.602). In SHF patients, allele frequencies of Gln41 and Leu41 were 446 (0.991) and 4 (0.009) (χ(2) = 0.018, P = 0.893), and allele frequencies of Arg389 and Gly389 were 331 (0.726) and 125 (0.274) (χ(2) = 1.892, P = 0.169). Further in logistic regression model, these ADRB1 and GRK5 variants were not significantly independently associated with the risk of SHF morbidity. Those carrying genotype ADRB1 Gly389Gly did not reduce significantly the risk of SHF morbidity after β-blocker therapy. CONCLUSIONS GRK5 Leu41Leu genotype was not found in our Chinese population, neither ADRB1 nor GRK5 variants presented independently associated with the risk of SHF morbidity, most ADRB1 and GRK5 polymorphisms did decrease significantly the risk of SHF morbidity after β-blocker therapy except for those carrying genotype ADRB1 Gly389Gly.
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Affiliation(s)
- Sheng Kang
- Department of cardiology, Shanghai East hospital, Tongji University, Jimo Rd 150, 200120, Shanghai, P. R. China.
| | - Xuan Hong
- Department of cardiology, Shanghai East hospital, Tongji University, Jimo Rd 150, 200120, Shanghai, P. R. China.
| | - Chang-wu Ruan
- Department of Cardiology, Shanghai the 8th People's Hospital, Caobao Road 8, 200235, Shanghai, China.
| | - Ping Yu
- Department of cardiology, Shanghai East hospital, Tongji University, Jimo Rd 150, 200120, Shanghai, P. R. China.
| | - Shan-shan Yu
- Department of Clinical Laboratory, Shanghai East Hospital, Tongji University, Jimo Rd 150, 200120, Shanghai, P. R. China.
| | - Ming Chen
- Department of cardiology, Shanghai East hospital, Tongji University, Jimo Rd 150, 200120, Shanghai, P. R. China.
| | - Dai-fu Zhang
- Department of Cardiology, Pudong New District People's Hospital, Chuan Ring Road 490, 201299, Shanghai, China.
| | - Hui-min Fan
- Department of cardiology, Shanghai East hospital, Tongji University, Jimo Rd 150, 200120, Shanghai, P. R. China.
| | - Zhong-min Liu
- Department of cardiology, Shanghai East hospital, Tongji University, Jimo Rd 150, 200120, Shanghai, P. R. China.
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Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways. Proc Natl Acad Sci U S A 2014; 111:16604-9. [PMID: 25368166 DOI: 10.1073/pnas.1415933111] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cardiac disorders are the main cause of mortality in autosomal-dominant polycystic kidney disease (ADPKD). However, how mutated polycystins predispose patients with ADPKD to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased levels of polycystin 2 (PC2), a calcium channel that interacts with the ryanodine receptor, on myocardial function. We hypothesize that heterozygous PC2 mice (Pkd2(+/-)) undergo cardiac remodeling as a result of changes in calcium handling, separate from renal complications. We found that Pkd2(+/-) cardiomyocytes have altered calcium handling, independent of desensitized calcium-contraction coupling. Paradoxically, in Pkd2(+/-) mice, protein kinase A (PKA) phosphorylation of phospholamban (PLB) was decreased, whereas PKA phosphorylation of troponin I was increased, explaining the decoupling between calcium signaling and contractility. In silico modeling supported this relationship. Echocardiography measurements showed that Pkd2(+/-) mice have increased left ventricular ejection fraction after stimulation with isoproterenol (ISO), a β-adrenergic receptor (βAR) agonist. Blockers of βAR-1 and βAR-2 inhibited the ISO response in Pkd2(+/-) mice, suggesting that the dephosphorylated state of PLB is primarily by βAR-2 signaling. Importantly, the Pkd2(+/-) mice were normotensive and had no evidence of renal cysts. Our results showed that decreased PC2 levels shifted the βAR pathway balance and changed expression of calcium handling proteins, which resulted in altered cardiac contractility. We propose that PC2 levels in the heart may directly contribute to cardiac remodeling in patients with ADPKD in the absence of renal dysfunction.
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50
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Lymperopoulos A, Garcia D, Walklett K. Pharmacogenetics of cardiac inotropy. Pharmacogenomics 2014; 15:1807-1821. [PMID: 25493572 DOI: 10.2217/pgs.14.120] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The ability to stimulate cardiac contractility is known as positive inotropy. Endogenous hormones, such as adrenaline and several natural or synthetic compounds possess this biological property, which is invaluable in the modern cardiovascular therapy setting, especially in acute heart failure or in cardiogenic shock. A number of proteins inside the cardiac myocyte participate in the molecular pathways that translate the initial stimulus, that is, the hormone or drug, into the effect of increased contractility (positive inotropy). Genetic variations (polymorphisms) in several genes encoding these proteins have been identified and characterized in humans with potentially significant consequences on cardiac inotropic function. The present review discusses these polymorphisms and their effects on cardiac inotropy, along with the individual pharmacogenomics of the most important positive inotropic agents in clinical use today. Important areas for future investigations in the field are also highlighted.
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Affiliation(s)
- Anastasios Lymperopoulos
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S. University Drive, HPD (Terry) Bldg/Room 1338, Ft. Lauderdale, FL 33328-2018, USA
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