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1
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Zeng C, Wu J, Li J. Pyruvate Kinase M2: A Potential Regulator of Cardiac Injury Through Glycolytic and Non-glycolytic Pathways. J Cardiovasc Pharmacol 2024; 84:1-9. [PMID: 38560918 PMCID: PMC11230662 DOI: 10.1097/fjc.0000000000001568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 03/18/2024] [Indexed: 04/04/2024]
Abstract
ABSTRACT Adult animals are unable to regenerate heart cells due to postnatal cardiomyocyte cycle arrest, leading to higher mortality rates in cardiomyopathy. However, reprogramming of energy metabolism in cardiomyocytes provides a new perspective on the contribution of glycolysis to repair, regeneration, and fibrosis after cardiac injury. Pyruvate kinase (PK) is a key enzyme in the glycolysis process. This review focuses on the glycolysis function of PKM2, although PKM1 and PKM2 both play significant roles in the process after cardiac injury. PKM2 exists in both low-activity dimer and high-activity tetramer forms. PKM2 dimers promote aerobic glycolysis but have low catalytic activity, leading to the accumulation of glycolytic intermediates. These intermediates enter the pentose phosphate pathway to promote cardiomyocyte proliferation and heart regeneration. Additionally, they activate adenosine triphosphate (ATP)-sensitive K + (K ATP ) channels, protecting the heart against ischemic damage. PKM2 tetramers function similar to PKM1 in glycolysis, promoting pyruvate oxidation and subsequently ATP generation to protect the heart from ischemic damage. They also activate KDM5 through the accumulation of αKG, thereby promoting cardiomyocyte proliferation and cardiac regeneration. Apart from glycolysis, PKM2 interacts with transcription factors like Jmjd4, RAC1, β-catenin, and hypoxia-inducible factor (HIF)-1α, playing various roles in homeostasis maintenance, remodeling, survival regulation, and neovascularization promotion. However, PKM2 has also been implicated in promoting cardiac fibrosis through mechanisms like sirtuin (SIRT) 3 deletion, TG2 expression enhancement, and activation of transforming growth factor-β1 (TGF-β1)/Smad2/3 and Jak2/Stat3 signals. Overall, PKM2 shows promising potential as a therapeutic target for promoting cardiomyocyte proliferation and cardiac regeneration and addressing cardiac fibrosis after injury.
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Affiliation(s)
- Chenxin Zeng
- The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, China
- Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, China
| | - Jiangfeng Wu
- The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, China; and
| | - Junming Li
- The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, China
- Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, China
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2
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Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther 2024; 9:61. [PMID: 38514615 PMCID: PMC10958066 DOI: 10.1038/s41392-024-01764-w] [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: 12/07/2022] [Revised: 08/31/2023] [Accepted: 01/31/2024] [Indexed: 03/23/2024] Open
Abstract
Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.
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Affiliation(s)
- Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yujia Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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3
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Zhou JX, Cheng AS, Chen L, Li LX, Agborbesong E, Torres VE, Harris PC, Li X. CD74 Promotes Cyst Growth and Renal Fibrosis in Autosomal Dominant Polycystic Kidney Disease. Cells 2024; 13:489. [PMID: 38534333 PMCID: PMC10968819 DOI: 10.3390/cells13060489] [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: 01/06/2024] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 03/28/2024] Open
Abstract
The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in Pkd1 mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease Pkd1 mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in Pkd1 mutant kidneys, and (3) decrease renal fibrosis in Pkd1 mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-β-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment.
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Affiliation(s)
- Julie Xia Zhou
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Alice Shasha Cheng
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Li Chen
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Linda Xiaoyan Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Ewud Agborbesong
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Vicente E. Torres
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Peter C. Harris
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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4
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Chen HY, Ko ML, Chan HL. Effects of hyperglycemia on the TGF-β pathway in trabecular meshwork cells. Biochim Biophys Acta Gen Subj 2024; 1868:130538. [PMID: 38072209 DOI: 10.1016/j.bbagen.2023.130538] [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: 05/23/2023] [Revised: 12/03/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND Hyperglycemia, which can lead to apoptosis, hypertrophy, fibrosis, and induces hyperinflammation in diabetic vascular complications due to oxidative stress. In order to elucidate the potential dual roles and regulatory signal transduction of TGF-β1 and TGF-β2 in human trabecular meshwork cells (HTMCs), we established an oxidative cell model in HTMCs using 5.5, 25, 50, and 100 mM d-glucose-supplemented media and characterized the TGF-β-related oxidative stress pathway. METHODS Further analysis was conducted to investigate oxidative damage and protein alterations in the HTMC caused by the signal transduction. This was done through a series of qualitative cell function studies, such as cell viability/apoptosis analysis, intracellular reactive oxygen species (ROS) detection, analysis of calcium release concentration, immunoblot analysis to detect the related protein expression alteration, and analysis of cell fibrosis to study the effect of different severities of hyperglycemia. Also, we illustrated the role of TGF-β1/2 in oxidative stress-induced injury by shRNA-mediated knockdown or stimulation with recombinant human TGF-β1 protein (rhTGF-β1). RESULTS Results from the protein expression analysis showed that p-JNK, p-p38, p-AKT, and related SMAD family members were upregulated in HTMCs under hyperglycemia. In the cell functional assays, HTMCs treated with rhTGFβ-1 (1 ng/mL) under hyperglycemic conditions showed higher proliferation rates and lower ROS and calcium levels. CONCLUSIONS To summarize, mechanistic analyses in HTMCs showed that hyperglycemia-induced oxidative stress activated TGF-β1 along with its associated pathway. GENERAL SIGNIFICANCE While at low concentrations, TGF-β1 protects cells from antioxidation, whereas at high concentrations, it accumulates in the extracellular matrix, causing further HTMC dysfunction.
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Affiliation(s)
- Hsin-Yi Chen
- Institute of Bioinformatics and Structural Biology & Department of Medical Sciences, National Tsing Hua University, Hsinchu 300, Taiwan
| | - Mei-Lan Ko
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan; Department of Ophthalmology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 300, Taiwan.
| | - Hong-Lin Chan
- Institute of Bioinformatics and Structural Biology & Department of Medical Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
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5
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Yu X. Promising Therapeutic Treatments for Cardiac Fibrosis: Herbal Plants and Their Extracts. Cardiol Ther 2023; 12:415-443. [PMID: 37247171 PMCID: PMC10423196 DOI: 10.1007/s40119-023-00319-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/27/2023] [Indexed: 05/30/2023] Open
Abstract
Cardiac fibrosis is closely associated with multiple heart diseases, which are a prominent health issue in the global world. Neurohormones and cytokines play indispensable roles in cardiac fibrosis. Many signaling pathways participate in cardiac fibrosis as well. Cardiac fibrosis is due to impaired degradation of collagen and impaired fibroblast activation, and collagen accumulation results in increasing heart stiffness and inharmonious activity, leading to structure alterations and finally cardiac function decline. Herbal plants have been applied in traditional medicines for thousands of years. Because of their naturality, they have attracted much attention for use in resisting cardiac fibrosis in recent years. This review sheds light on several extracts from herbal plants, which are promising therapeutics for reversing cardiac fibrosis.
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Affiliation(s)
- Xuejing Yu
- Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75235, USA.
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6
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Qin Y, Ye X, Luo Y, Peng L, Zhou G, Zhu Y, Pan C. hKLK alleviates myocardial fibrosis in mice with viral myocarditis. J Appl Biomed 2023; 21:15-22. [PMID: 37016776 DOI: 10.32725/jab.2023.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 03/24/2023] [Indexed: 04/05/2023] Open
Abstract
Myocardial fibrosis is the most serious complication of viral myocarditis (VMC). This study aimed to investigate the therapeutic benefits and underlying mechanisms of lentivirus-mediated human tissue kallikrein gene transfer in myocardial fibrosis in VMC mice. We established VMC mouse model via intraperitoneal injection with Coxsackie B3 virus. The effect was then assessed after treatment with vehicle, the empty lentiviral vectors (EZ.null), and the vectors expressing hKLK1 (EZ.hKLK1) via tail vein injection for 30 days, respectively. The results showed that administering EZ.hKLK1 successfully induced hKLK1 overexpression in mouse heart. Compared with EZ.null treatment, EZ.hKLK1 administration significantly reduced the heart/weight ratio, improved cardiac function, and ameliorated myocardial inflammation in VMC mice, suggesting that hKLK1 overexpression alleviates VMC in mice. EZ.hKLK1 administration also significantly abrogated the increased myocardial collagen content, type I/III collagen ratio, TGF-β1 mRNA and protein expression in VMC mice, suggesting that hKLK1 overexpression reduces collagen accumulation and blunts TGF-β1 signaling in the hearts of VMC mice. In conclusion, our results suggest that hKLK1 alleviates myocardial fibrosis in VMC mice, possibly by downregulating TGF-β1 expression.
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7
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Hajializadeh Z, Khaksari M, Dabiri S, Darvishzadeh Mahani F, Raji-Amirhasani A, Bejeshk MA. Protective effects of calorie restriction and 17-β estradiol on cardiac hypertrophy in ovariectomized obese rats. PLoS One 2023; 18:e0282089. [PMID: 37098007 PMCID: PMC10128952 DOI: 10.1371/journal.pone.0282089] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 02/06/2023] [Indexed: 04/26/2023] Open
Abstract
Obesity and menopause lead to cardiovascular diseases. Calorie restriction (CR) can modulate estrogen deficiency and obesity-related cardiovascular diseases. The protective effects of CR and estradiol on cardiac hypertrophy in ovariectomized obese rats were explored in this study. The adult female Wistar rats were divided into sham and ovariectomized (OVX) groups that received a high-fat diet (60% HFD) or standard diet (SD) or 30% CR for 16 weeks, and then, 1mg/kg E2 (17-β estradiol) was injected intraperitoneally every 4 days for four weeks in OVX-rats. Hemodynamic parameters were evaluated before and after each diet. Heart tissues were collected for biochemical, histological, and molecular analysis. HFD consumption led to weight gain in sham and OVX rats. In contrast, CR and E2 led to body weight loss in these animals. Also, heart weight (HW), heart weight/body weight (HW/BW) ratio, and left ventricular weight (LVW) were enhanced in OVX rats that received SD and HFD. E2 reduced these indexes in both diet conditions but reduction effects of CR were seen only in HFD groups. HFD and SD feeding increased hemodynamic parameters, ANP (atrial natriuretic peptide) mRNA expression, and TGF-β1(transforming growth factor-beta 1) protein level in the OVX animals, while CR and E2 reduced these factors. Cardiomyocyte diameter and hydroxyproline content were increased in the OVX-HFD groups. Nevertheless, CR and E2 decreased these indicators. The results showed that CR and E2 treatment reduced obesity-induced-cardiac hypertrophy in ovariectomized groups (20% and 24% respectively). CR appears to have almost as reducing effects as estrogen therapy on cardiac hypertrophy. The findings suggest that CR can be considered a therapeutic candidate for postmenopausal cardiovascular disease.
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Affiliation(s)
- Zahra Hajializadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences Kerman, Kerman, Iran
| | - Shahriar Dabiri
- Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Darvishzadeh Mahani
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences Kerman, Kerman, Iran
| | - Alireza Raji-Amirhasani
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences Kerman, Kerman, Iran
| | - Mohammad Abbas Bejeshk
- Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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8
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Ikeda M, Ide T, Matsushima S, Ikeda S, Okabe K, Ishikita A, Tadokoro T, Sada M, Abe K, Sato M, Hanada A, Arai S, Ohtani K, Nonami A, Mizuno S, Morimoto S, Motohashi S, Akashi K, Taniguchi M, Tsutsui H. Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model. Circ Heart Fail 2022; 15:e009366. [PMID: 36268712 PMCID: PMC9760469 DOI: 10.1161/circheartfailure.122.009366] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Dilated cardiomyopathy (DCM) is a life-threatening disease, resulting in refractory heart failure. An immune disorder underlies the pathophysiology associated with heart failure progression. Invariant natural killer T (iNKT) cell activation is a prospective therapeutic strategy for ischemic heart disease. However, its efficacy in nonischemic cardiomyopathy, such as DCM, remains to be elucidated, and the feasible modality for iNKT cell activation in humans is yet to be validated. METHODS Dendritic cells isolated from human volunteers were pulsed with α-galactosylceramide ex vivo, which were used as α-galactosylceramide-pulsed dendritic cells (αGCDCs). We treated DCM mice harboring mutated troponin TΔK210/ΔK210 with αGCDCs and evaluated the efficacy of iNKT cell activation on heart failure in DCM mice. Furthermore, we investigated the molecular basis underlying its therapeutic effects in these mice and analyzed primary cardiac cells under iNKT cell-secreted cytokines. RESULTS The number of iNKT cells in the spleens of DCM mice was reduced compared with that in wild-type mice, whereas αGCDC treatment activated iNKT cells, prolonged survival of DCM mice, and prevented decline in the left ventricular ejection fraction for 4 weeks, accompanied by suppressed interstitial fibrosis. Mechanistically, αGCDC treatment suppressed TGF (transforming growth factor)-β signaling and expression of fibrotic genes and restored vasculature that was impaired in DCM hearts by upregulating angiopoietin 1 (Angpt1) expression. Consistently, IFNγ (interferon gamma) suppressed TGF-β-induced Smad2/3 signaling and the expression of fibrotic genes in cardiac fibroblasts and upregulated Angpt1 expression in cardiomyocytes via Stat1. CONCLUSIONS Immunomodulatory cell therapy with αGCDCs is a novel therapeutic strategy for heart failure in DCM.
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Affiliation(s)
- Masataka Ikeda
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Immunoregulatory Cardiovascular Medicine (M.I., T.I.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomomi Ide
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Immunoregulatory Cardiovascular Medicine (M.I., T.I.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shouji Matsushima
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Soichiro Ikeda
- Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kosuke Okabe
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akihito Ishikita
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomonori Tadokoro
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masashi Sada
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ko Abe
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Midori Sato
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akiko Hanada
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinobu Arai
- Department of Early Childhood and Elementary Education, Faculty of Education, Nakamura Gakuen University, Fukuoka, Japan (S.A.)
| | - Kisho Ohtani
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsushi Nonami
- Center for Advanced Medical Innovation, Kyushu University Hospital, Fukuoka, Japan (A.N.)
| | - Shinichi Mizuno
- Department of Health Sciences (S. Mizuno), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sachio Morimoto
- Department of Health Sciences at Fukuoka, International University of Health and Welfare, Japan (S. Morimoto)
| | - Shinichiro Motohashi
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Medical Immunology, Graduate School of Medicine, Chiba University, Japan (S. Motohashi)
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science (K. Akashi), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaru Taniguchi
- Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (M.T.)
| | - Hiroyuki Tsutsui
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
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9
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Li LX, Agborbesong E, Zhang L, Zhang X, Zhou JX, Li X. Crosstalk between lysine methyltransferase Smyd2 and TGF-β-Smad3 signaling promotes renal fibrosis in autosomal dominant polycystic kidney disease. Am J Physiol Renal Physiol 2022; 323:F227-F242. [PMID: 35759739 PMCID: PMC9359663 DOI: 10.1152/ajprenal.00452.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disorder, which is caused by mutations of PKD1 or PKD2 gene and is characterized by renal fluid-filled cyst formation and interstitial fibrosis. PKD1 gene mutation results in the upregulation of SET and MYND domain-containing lysine methyltransferase 2 (SMYD2) in Pkd1 mutant mouse and ADPKD patient kidneys. However, the role and mechanism of Smyd2 in the regulation of renal fibrosis in ADPKD remains elusive. In this study, we show that: 1) the expression of Smyd2 can be regulated by TGF-β-Smad3 in normal rat kidney 49F (NRK-49F) cells and mouse fibroblast NIH3T3 cells; 2) knockdown of Smyd2 and inhibition of Smyd2 with its specific inhibitor, AZ505, decreases TGF-β-induced expression of α-smooth muscle actin (α-SMA), fibronectin, collagens 1 and 3 and plasminogen activator inhibitor-1( PAI1) in NRK-49F cells; 3) Smyd2 regulates the transcription of fibrotic marker genes through binding on the promoters of those genes or through methylating histone H3 to indirectly regulate the expression of those genes; and 4) knockout and inhibition of Smyd2 significantly decreases renal fibrosis in Pkd1 knockout mice, supporting that targeting Smyd2 can not only delay cyst growth but also attenuate renal fibrosis in ADPKD. This study identifies a crosstalk between TGF-β signaling and Smyd2 in the regulation of fibrotic gene transcription and the activation of fibroblasts in cystic kidneys, suggesting that targeting Smyd2 with AZ505 is a potential therapeutic strategy for ADPKD treatment.
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Affiliation(s)
- Linda Xiaoyan Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
| | - Ewud Agborbesong
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
| | - Lu Zhang
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
| | - Xiaoqin Zhang
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
| | - Julie Xia Zhou
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
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10
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Zhang X, Zheng C, Gao Z, Wang L, Chen C, Zheng Y, Meng Y. PKM2 promotes angiotensin-II-induced cardiac remodelling by activating TGF-β/Smad2/3 and Jak2/Stat3 pathways through oxidative stress. J Cell Mol Med 2021; 25:10711-10723. [PMID: 34687136 PMCID: PMC8581335 DOI: 10.1111/jcmm.17007] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 09/24/2021] [Accepted: 10/04/2021] [Indexed: 12/30/2022] Open
Abstract
Hypertensive cardiac remodelling is a common cause of heart failure. However, the molecular mechanisms regulating cardiac remodelling remain unclear. Pyruvate kinase isozyme type M2 (PKM2) is a key regulator of the processes of glycolysis and oxidative phosphorylation, but the roles in cardiac remodelling remain unknown. In the present study, we found that PKM2 was enhanced in angiotensin II (Ang II)-treated cardiac fibroblasts and hypertensive mouse hearts. Suppression of PKM2 by shikonin alleviated cardiomyocyte hypertrophy and fibrosis in Ang-II-induced cardiac remodelling in vivo. Furthermore, inhibition of PKM2 markedly attenuated the function of cardiac fibroblasts including proliferation, migration and collagen synthesis in vitro. Mechanistically, suppression of PKM2 inhibited cardiac remodelling by suppressing TGF-β/Smad2/3, Jak2/Stat3 signalling pathways and oxidative stress. Together, this study suggests that PKM2 is an aggravator in Ang-II-mediated cardiac remodelling. The negative modulation of PKM2 may provide a promising therapeutic approach for hypertensive cardiac remodelling.
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Affiliation(s)
- Xiyu Zhang
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing Lab for Cardiovascular Precision Medicine, Department of Pathology, Capital Medical University, Beijing, China
| | - Cuiting Zheng
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing Lab for Cardiovascular Precision Medicine, Department of Pathology, Capital Medical University, Beijing, China
| | - Zhenqiang Gao
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing Lab for Cardiovascular Precision Medicine, Department of Pathology, Capital Medical University, Beijing, China
| | - Lingling Wang
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Chen Chen
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Yuanyuan Zheng
- Department of Pharmacology, Capital Medical University, Beijing, China
| | - Yan Meng
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing Lab for Cardiovascular Precision Medicine, Department of Pathology, Capital Medical University, Beijing, China
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11
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Celecoxib alleviates pathological cardiac hypertrophy and fibrosis via M1-like macrophage infiltration in neonatal mice. iScience 2021; 24:102233. [PMID: 33748715 PMCID: PMC7967012 DOI: 10.1016/j.isci.2021.102233] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 01/13/2021] [Accepted: 02/22/2021] [Indexed: 12/26/2022] Open
Abstract
Cardiac hypertrophy is an adaptive response to all forms of heart disease, including hypertension, myocardial infarction, and cardiomyopathy. Cyclooxygenase-2 (COX-2) overexpression results in inflammatory response, cardiac cell apoptosis, and hypertrophy in adult heart after injury. However, immune response-mediated cardiac hypertrophy and fibrosis have not been well documented in injured neonatal heart. This study showed that cardiac hypertrophy and fibrosis are significantly attenuated in celecoxib (a selective COX-2 inhibitor)-treated P8 ICR mice after cryoinjury. Molecular and cellular profiling of immune response shows that celecoxib inhibits the production of cytokines and the expression of adhesion molecular genes, increases the recruitment of M1-like macrophage at wound site, and alleviates cardiac hypertrophy and fibrosis. Furthermore, celecoxib administration improves cardiac function at 4 weeks after injury. These results demonstrate that COX-2 inhibition promotes the recruitment of M1-like macrophages during early wound healing, which may contribute to the suppression of cardiac hypertrophy and fibrosis after injury.
Cryoinjury successfully induces cardiac hypertrophy and fibrosis in P8 ICR mice COX-2 inhibition alleviates cardiac hypertrophy and fibrosis after cryoinjury MCP-1 significantly increases in COX-2 inhibition COX-2 inhibition improves cardiac repair in P8 ICR mice by recruiting M1-like macrophages
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12
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Lv S, Yuan P, Lu C, Dong J, Li M, Qu F, Zhu Y, Zhang J. QiShenYiQi pill activates autophagy to attenuate reactive myocardial fibrosis via the PI3K/AKT/mTOR pathway. Aging (Albany NY) 2021; 13:5525-5538. [PMID: 33582656 PMCID: PMC7950250 DOI: 10.18632/aging.202482] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/20/2020] [Indexed: 01/08/2023]
Abstract
QiShenYiQi pill (QSYQ), a traditional Chinese medicine, is used to treat cardiovascular diseases. However, the dose-effect relationship of its intervention in the reactive myocardial fibrosis is elusive. In this work, rat models of reactive myocardial fibrosis induced by partial abdominal aortic coarctation were constructed and randomly classified into the model group, 3-methyladenine group, rapamycin group, QSYQ low-dose group, QSYQ medium-dose group, QSYQ high-dose group, and sham-operated rats (control group). We revealed that QSYQ lowered the heart mass index (HMI), left ventricular mass index (LVMI), and myocardial collagen volume fraction (CVF) levels in a dose-dependent mechanism. Additionally, QSYQ increased the number of autophagosomes, and the expression of myocardial Beclin-1 and LC3B. In contrast, it reduced the expression of myocardial p62 and decreased the ratios of myocardial p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR. In conclusion, our results have revealed that QSYQ impacts anti-reactive myocardial fibrosis in a dose-dependent mechanism which is mediated by the activation of myocardial autophagy via the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Shichao Lv
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
- Tianjin Key Laboratory of Traditional Research of TCM Prescription and Syndrome, Tianjin 300193, China
| | - Peng Yuan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Chunmiao Lu
- Jiashan Hospital of Traditional Chinese Medicine, Jiaxing 314100, Zhejiang, China
| | - Jianping Dong
- Health Center of Balitai Town, Jinnan, Tianjin 300350, China
| | - Meng Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Fan Qu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Yaping Zhu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Junping Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
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13
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Chakraborti S, Pramanick A, Saha S, Sarkar S, Singh LP, Stewart A, Maity B. Biphasic changes in TGF-β1 signaling drive NSAID-induced multi-organ damage. Free Radic Biol Med 2020; 160:125-140. [PMID: 32750407 DOI: 10.1016/j.freeradbiomed.2020.06.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 06/04/2020] [Accepted: 06/18/2020] [Indexed: 12/15/2022]
Abstract
The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs), used extensively worldwide, is limited by adverse cardiac events resulting from chronic drug exposure. Here, we provide evidence identifying transforming growth factor β (TGF-β1), released from multiple tissues, as a critical driver of NSAID-induced multi-organ damage. Biphasic changes in TGF-β1 levels in liver and heart were accompanied by ROS generation, cell death, fibrotic remodeling, compromised cardiac contractility and elevated liver enzymes. Pharmacological inhibition of TGF-βRI signaling markedly improved heart and liver function and increased overall survival of animals exposed to multiple NSAIDs, effects likely mediated by reductions in NOX-dependent ROS generation. Notably, the beneficial impact of TGF-βRI blockade was confined to a critical window wherein consecutive, but not concurrent, inhibitor administration improved cardiac and hepatic endpoints. Remarkably, in addition to ameliorating indomethacin-mediated myofilament disruptions, cardiac TGF-βRI knockdown lead to drastic reductions in TGF-β1 production accompanied by lessening in intestinal lesioning underscoring the importance of endocrine TGF-β1 signaling in NSAID-driven tissue injury. Indeed, gastric ulceration was associated with a higher incidence of cardiac complications in a human cohort underscoring the critical importance of circulation-facilitated peripheral organ system interconnectedness in efforts seeking to mitigate the toxic side effects of chronic NSAID use.
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Affiliation(s)
- Sreemoyee Chakraborti
- Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India
| | - Arnab Pramanick
- Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India
| | - Sudipta Saha
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Subhasish Sarkar
- Department of Surgery, College of Medicine and Sagore Dutta Hospital, B.T. Road, Kamarhati, Kolkata, West Bengal, 700058, India
| | | | - Adele Stewart
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, 33458, USA.
| | - Biswanath Maity
- Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
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14
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Jian J, Zhang P, Li Y, Liu B, Zhang Y, Zhang L, Shao XM, Zhuang J, Xiao D. Reprogramming of miR-181a/DNA methylation patterns contribute to the maternal nicotine exposure-induced fetal programming of cardiac ischemia-sensitive phenotype in postnatal life. Theranostics 2020; 10:11820-11836. [PMID: 33052248 PMCID: PMC7546014 DOI: 10.7150/thno.48297] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023] Open
Abstract
Background: E-cigarette and other novel electronic nicotine delivery systems (ENDS) have recently entered the market at a rapid pace. The community desperately needs answers about the health effects of ENDS. The present study tested the hypothesis that perinatal nicotine exposure (PNE) causes a gender-dependent increase in vulnerability of the heart to ischemia-reperfusion (I/R) injury and cardiac dysfunction in male rat offspring via reprogramming of the miRNA-181a (miR-181a)-mediated signaling pathway and that miR-181a antisense could rescue this phenotype. Methods: Nicotine or saline was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. Cardiac function and molecular biological experiments were conducted in ~3- month-old offspring. Results: PNE enhanced I/R-induced cardiac dysfunction and infarction in adult male but not in female offspring, which was associated with miR-181a over-expression in left ventricle tissues. In addition, PNE enhanced offspring cardiac angiotensin receptor (ATR) expressions via specific CpG hypomethylation of AT1R/AT2R promoter. Furthermore, PNE attenuated cardiac lncRNA H19 levels, but up-regulated cardiac TGF-β/Smads family proteins and consequently up-regulated autophagy-related protein (Atg-5, beclin-1, LC3 II, p62) expression in the male offspring. Of importance, treatment with miR-181a antisense eliminated the PNE's effect on miR-181a expression/H19 levels and reversed PNE-mediated I/R-induced cardiac infarction and dysfunction in male offspring. Furthermore, miR-181a antisense also attenuated the effect of PNE on AT1R/AT2R/TGF-β/Smads/autophagy-related biomarkers in the male offspring. Conclusion: Our data suggest that PNE could induce a reprogramming of cardiac miR-181a expression/DNA methylation pattern, which epigenetically modulates ATR/TGF-β/autophagy signaling pathways, leading to gender-dependent development of ischemia-sensitive phenotype in postnatal life. Furthermore, miR-181a could severe as a potential therapeutic target for rescuing this phenotype.
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15
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EphrinA1-Fc Attenuates Ventricular Remodeling and Dysfunction in Chronically Nonreperfused WT but not EphA2-R-M mice. Int J Mol Sci 2020; 21:ijms21165811. [PMID: 32823610 PMCID: PMC7461052 DOI: 10.3390/ijms21165811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 08/08/2020] [Accepted: 08/11/2020] [Indexed: 12/21/2022] Open
Abstract
Background: EphrinA1-Fc abolishes acute I/R injury and attenuates nonreperfused cardiac injury 4 days after permanent occlusion in mice. The goal of this study was to assess the capacity of a single intramyocardial administration of ephrinA1-Fc at the time of coronary artery ligation, to determine the degree to which early salvage effects translate to reduced adverse remodeling after 4 weeks of nonreperfused myocardial infarction (MI) in wild-type B6 and EphA2-R-M (EphA2 receptor null) mice. Methods: At 4 weeks post-MI, echocardiography, histologic and immunohistochemical analyses of B6 mouse hearts were performed. Primary mouse cardiac fibroblasts (FBs) isolated from B6 mice cultured in the presence of low and high dose ephrinA1-Fc, both with and without pro-fibrotic TGF-β stimulation and Western blots, were probed for relative expression of remodeling proteins MMP-2, MMP-9 and TIMP-1, in addition to DDR2 and (p)SMAD2/3/totalSMAD2/3. Results: EphrinA1-Fc preserved a significant degree of contractile function, decreased adverse left ventricular remodeling, attenuated excessive compensatory hypertrophy, and decreased interstitial fibrosis in wild-type (WT) B6 mouse hearts. In contrast, most of these parameters were poorer in ephrinA1-Fc-treated EphA2-R-M mice. Of note, fibrosis was proportionately decreased, implying that other EphA receptor(s) are more important in regulating the pro-fibrotic response. Primary FBs showed disparate alteration of MMP-2, MMP-9 and TIMP-1, as well as DDR2 and p-SMAD2/3/totalSMAD2/3, which indicates that matrix remodeling and cardiac fibrosis in the injured heart are influenced by ephrinA1-Fc. Conclusion: This study demonstrates the capacity of a single administration of ephrinA1-Fc at the onset of injury to attenuate long-term nonreperfused post-MI ventricular remodeling that results in progressive heart failure, and the important role of EphA2 in mitigating the deleterious effects.
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16
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Peterson MR, Getiye Y, Bosch L, Sanders AJ, Smith AR, Haller S, Wilson K, Paul Thomas D, He G. A potential role of caspase recruitment domain family member 9 (Card9) in transverse aortic constriction-induced cardiac dysfunction, fibrosis, and hypertrophy. Hypertens Res 2020; 43:1375-1384. [PMID: 32647279 DOI: 10.1038/s41440-020-0507-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 05/29/2020] [Accepted: 06/11/2020] [Indexed: 12/24/2022]
Abstract
Macrophage- and monocyte-derived cytokines are elevated in the myocardium of pressure-overloaded hearts, where they play critical roles in pathological remodeling. Caspase recruitment domain family member 9 (CARD9) regulates macrophage cytokine secretion, but its role in a transverse aortic constriction (TAC) model of pressure overload has not been evaluated. To investigate whether CARD9 may serve as a valuable therapeutic target, wild-type (WT) and CARD9-knockout mice were subjected to 3 months of TAC, and then cardiac function, hypertrophy, and fibrosis were analyzed. The expression of protein markers of myocardial autophagy and nuclear factor kappa B signaling was also investigated. At 1 month after TAC, cardiomyocyte contractile dynamics were measured in a separate cohort to further assess contractility and diastolic function. In WT but not CARD9-/- mice, TAC resulted in severe cardiomyocyte contractile dysfunction at 1 month and functional decrements in fractional shortening at 3 months in vivo. Furthermore, CARD9-/- mice did not develop cardiac fibrosis or hypertrophy. CARD9-/- mice also had decreased protein expression of inhibitor of κB kinase-α/β, decreased phosphorylation of p65, and increased expression of protein markers of autophagy. These findings suggest that CARD9 plays a role in pathological remodeling and cardiac dysfunction in mouse hearts subjected to TAC and should be investigated further.
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Affiliation(s)
- Matthew R Peterson
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Yohannes Getiye
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Luiza Bosch
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Alyssa J Sanders
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Aspen R Smith
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Samantha Haller
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Kayla Wilson
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - D Paul Thomas
- Division of Kinesiology & Health, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Guanglong He
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA.
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17
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Shepel RN, Drapkina OM. Angiogenesis in Patients with Chronic Heart Failure: Focus on Endothelial Vascular Growth Factor, Pentraxin-3 and Transforming Growth Factor Beta. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2020. [DOI: 10.20996/1819-6446-2020-05-02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chronic heart failure (CHF) is considered the leading cause of death in patients with established cardiovascular (CVD) and metabolic diseases. Although the current treatment strategy has improved survival and clinical outcomes, the prevalence of CHF shows an increase. Current clinical guidelines for the treatment and prevention of CVD note the role of biological markers as a fairly simple and powerful tool for diagnosing, stratifying risk and predicting CHF. However, it is unclear whether all of these biological markers are equally capable of predicting cardiovascular mortality and heart failure related outcomes in patients with acute and chronic heart failure, as well as in different phenotypes of heart failure. However, the results of numerous studies demonstrate scientific interest in the processes of angiogenesis among patients with CHF. There is an impressive body of evidence linking CHF to the level of markers such as vascular endothelial growth factor, pentraxin-3, and transforming growth factor beta. The review presents the data of domestic and foreign clinical studies devoted to the study of the level of angiogenesis markers among patients with CHF.
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Affiliation(s)
- R. N. Shepel
- National Medical Research Center for Therapy and Preventive Medicine
| | - O. M. Drapkina
- National Medical Research Center for Therapy and Preventive Medicine
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18
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Chen Q, Zhang D, Bi Y, Zhang W, Zhang Y, Meng Q, Li Y, Bian H. The protective effects of liguzinediol on congestive heart failure induced by myocardial infarction and its relative mechanism. Chin Med 2020; 15:63. [PMID: 32549908 PMCID: PMC7296683 DOI: 10.1186/s13020-020-00345-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/07/2020] [Indexed: 12/16/2022] Open
Abstract
Background Heart failure (HF) is one of the most common causes of cardiovascular diseases in the world. Currently, the drugs used to treat HF in the clinic may cause serious side effects. Liguzinediol, 2, 5-dimethyl-3, 6-dimethyl-pyrazine, is a compound synthesized after the structural modification of ligustrazine (one active ingredient of Szechwan Lovage Rhizome). We aimed to observe the effects of liguzinediol on preventing HF and explore the related mechanisms. Methods The ligation of left anterior descending coronary artery was operated to established the myocardial infarction (MI) model in Sprague–Dawley rats. Cardiac functions were recorded by echocardiography and hemodynamics. The changes in the Renin–Angiotensin–Aldosterone System (RAAS), inflammation, and oxidative stress were detected by radioimmunoassay and Elisa kits. Western blot and real-time PCR were applied to determine the expressions of the TGF-β1/Smads pathway. Results Firstly, liguzinediol enhanced the systolic and diastolic functions of the heart in MI rats. Liguzinediol improved ventricular remodeling by reducing myocardial cell necrosis, as well as reducing collagen deposition and myocardial fibrosis. Then, liguzinediol suppressed the activation of RAAS, inhibited the synthesis of pro-inflammation factors, and reduced oxidative stress. In the end, liguzinediol also down-regulated the expressions of the TGF-β1/Smads pathway. Conclusions Liguzinediol could alleviate HF caused by MI in rats, and the protective effect was associated with the regulation of the TGF-β1/Smads pathway.![]()
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Affiliation(s)
- Qi Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Avenue, Qixia District, Nanjing, 210023 Jiangsu China
| | - Dini Zhang
- Key Laboratory on Biosafety, Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing, 210042 China
| | - Yunhui Bi
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Avenue, Qixia District, Nanjing, 210023 Jiangsu China
| | - Weiwei Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Avenue, Qixia District, Nanjing, 210023 Jiangsu China
| | - Yuhan Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Avenue, Qixia District, Nanjing, 210023 Jiangsu China
| | - Qinghai Meng
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Avenue, Qixia District, Nanjing, 210023 Jiangsu China
| | - Yu Li
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Xianlin Avenue, Qixia District, Nanjing, 210023 Jiangsu China
| | - Huimin Bian
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Avenue, Qixia District, Nanjing, 210023 Jiangsu China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
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19
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Nam JM, Lim JE, Ha TW, Oh B, Kang JO. Cardiac-specific inactivation of Prdm16 effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes. Am J Physiol Heart Circ Physiol 2020; 318:H764-H777. [PMID: 32083975 DOI: 10.1152/ajpheart.00647.2019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A variant in the PRDM16 locus has been correlated with QRS duration in an electrocardiogram genome-wide association study, and the deletion of PRDM16 has been implicated as a causal factor of the dilated cardiomyopathy that is linked to 1p36 deletion syndrome. We aimed to determine how a null mutation of Prdm16 affects cardiac function and study the underlying mechanism of the resulting phenotype in an appropriate mouse model. We used cardiac-specific Prdm16 conditional knockout mice to examine cardiac function by electrocardiography. QRS duration and QTc interval increased significantly in cardiac-specific Prdm16 knockout animals compared with wild-type mice. Further, we assessed cardiomyopathy-associated features by trichrome staining, densitometry, and hydroxyproline assay. Prdm16-null hearts showed greater fibrosis and cardiomyocyte hypertrophy. By quantitative real-time PCR, Prdm16-null hearts upregulated extracellular matrix-related genes (Ctgf, Timp1) and α-smooth muscle actin (Acta2), a myofibroblast marker. Moreover, TGF-β signaling was activated in Prdm16-null hearts, as evidenced by increased Tgfb1-3 transcript levels and phosphorylated Smad2. However, the inhibition of TGF-β receptor did not reverse the aberrations in conduction in cardiac-specific Prdm16 knockout mice. To determine the underlying mechanisms, we performed RNA-seq using mouse left ventricular tissue. By functional analysis, Prdm16-null hearts experienced dysregulated expression of ion channel genes, including Kcne1, Scn5a, Cacna1h, and Cacna2d2. Mice with Prdm16-null hearts develop abnormalities in cardiac conduction and cardiomyopathy-associated phenotypes, including fibrosis and cellular hypertrophy. Further, the RNA-seq findings suggest that impairments in ion homeostasis (Ca2+, K+, and Na+) may at least partially underlie the abnormal conduction in cardiac-specific Prdm16 knockout mice.NEW & NOTEWORTHY This is the first study that describes aberrant cardiac function and cardiomyopathy-associated phenotypes in an appropriate murine genetic model with cardiomyocyte-specific Prdm16-null mutation. It is noteworthy that the correlation of PRDM16 with QRS duration is replicated in a murine animal model and the potential underlying mechanism may be the impairment of ion homeostasis.
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Affiliation(s)
- Jeong Min Nam
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Ji Eun Lim
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Tae Woong Ha
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Bermseok Oh
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Ji-One Kang
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea
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Zou B, Schuster JP, Niu K, Huang Q, Rühle A, Huber PE. Radiotherapy-induced heart disease: a review of the literature. PRECISION CLINICAL MEDICINE 2019; 2:270-282. [PMID: 35693876 PMCID: PMC8985808 DOI: 10.1093/pcmedi/pbz025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 11/20/2022] Open
Abstract
Radiotherapy as one of the four pillars of cancer therapy plays a critical role in the multimodal treatment of thoracic cancers. Due to significant improvements in overall cancer survival, radiotherapy-induced heart disease (RIHD) has become an increasingly recognized adverse reaction which contributes to major radiation-associated toxicities including non-malignant death. This is especially relevant for patients suffering from diseases with excellent prognosis such as breast cancer or Hodgkin's lymphoma, since RIHD may occur decades after radiotherapy. Preclinical studies have enriched our knowledge of many potential mechanisms by which thoracic radiotherapy induces heart injury. Epidemiological findings in humans reveal that irradiation might increase the risk of cardiac disease at even lower doses than previously assumed. Recent preclinical studies have identified non-invasive methods for evaluation of RIHD. Furthermore, potential options preventing or at least attenuating RIHD have been developed. Ongoing research may enrich our limited knowledge about biological mechanisms of RIHD, identify non-invasive early detection biomarkers and investigate potential treatment options that might attenuate or prevent these unwanted side effects. Here, we present a comprehensive review about the published literature regarding clinical manifestation and pathological alterations in RIHD. Biological mechanisms and treatment options are outlined, and challenges in RIHD treatment are summarized.
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Affiliation(s)
- Bingwen Zou
- Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg 69120, Germany
- Department of Molecular Radiation Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany
| | - Julius Philipp Schuster
- Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg 69120, Germany
- Department of Molecular Radiation Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany
| | - Kerun Niu
- Department of Molecular Radiation Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany
| | - Qianyi Huang
- Department of Molecular Radiation Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany
| | - Alexander Rühle
- Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg 69120, Germany
- Department of Molecular Radiation Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany
- Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Oncology (NCRO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
| | - Peter Ernst Huber
- Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg 69120, Germany
- Department of Molecular Radiation Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany
- Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Oncology (NCRO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
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Asiatic acid inhibits cardiac fibrosis throughNrf2/HO-1 and TGF-β1/Smads signaling pathways in spontaneous hypertension rats. Int Immunopharmacol 2019; 74:105712. [DOI: 10.1016/j.intimp.2019.105712] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 05/26/2019] [Accepted: 06/18/2019] [Indexed: 01/13/2023]
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Bruns DR, Tatman PD, Kalkur RS, Brown RD, Stenmark KR, Buttrick PM, Walker LA. The right ventricular fibroblast secretome drives cardiomyocyte dedifferentiation. PLoS One 2019; 14:e0220573. [PMID: 31374110 PMCID: PMC6677314 DOI: 10.1371/journal.pone.0220573] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/18/2019] [Indexed: 12/14/2022] Open
Abstract
RATIONALE In virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We've previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells. OBJECTIVE To determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture. METHODS AND RESULTS Brief exposure (<2 days) to PH-CM results in rapid, marked dedifferentiation of ARVM to a neonatal-like phenotype exhibiting spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI and α-actinin yet exhibit myofibroblast characteristics including expression of α-smooth muscle actin. Using a bioinformatics approach to identify factor(s) that contribute to dedifferentiation, we found activation of the PH Cfib results in a unique transcriptome correlating with factors both in the secretome and with activated pathways in the dedifferentiated myocyte. Further, we identified upregulation of periostin in the Cfib and CM, and demonstrate that periostin is sufficient to drive cardiomyocyte dedifferentiation. CONCLUSIONS These data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction.
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Affiliation(s)
- Danielle R. Bruns
- University of Colorado-Denver, Dept. of Medicine/Cardiology, Aurora, CO, United States of America
| | - Philip D. Tatman
- University of Colorado-Denver, Dept. of Medicine/Cardiology, Aurora, CO, United States of America
- Medical Scientist Training Program, Aurora, CO, United States of America
| | - Roshni S. Kalkur
- University of Colorado-Denver, Dept. of Medicine/Cardiology, Aurora, CO, United States of America
| | - R. Dale Brown
- University of Colorado-Denver, Dept. of Pediatrics, Aurora, CO, United States of America
| | - Kurt R. Stenmark
- University of Colorado-Denver, Dept. of Pediatrics, Aurora, CO, United States of America
| | - Peter M. Buttrick
- University of Colorado-Denver, Dept. of Medicine/Cardiology, Aurora, CO, United States of America
| | - Lori A. Walker
- University of Colorado-Denver, Dept. of Medicine/Cardiology, Aurora, CO, United States of America
- * E-mail:
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Hu WS, Ting WJ, Tamilselvi S, Day CH, Wang T, Chiang WD, Viswanadha VP, Yeh YL, Lin WT, Huang CY. Oral administration of alcalase potato protein hydrolysate-APPH attenuates high fat diet-induced cardiac complications via TGF-β/GSN axis in aging rats. ENVIRONMENTAL TOXICOLOGY 2019; 34:5-12. [PMID: 30240538 DOI: 10.1002/tox.22651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 08/23/2018] [Accepted: 08/25/2018] [Indexed: 06/08/2023]
Abstract
Consumption of high fat diet (HFD) is associated with increased cardiovascular risk factors among elderly people. Aging and obesity induced-cardiac remodeling includes hypertrophy and fibrosis. Gelsolin (GSN) induces cardiac hypertrophy and TGF-β, a key cytokine, which induces fibrosis. The relationship between TGF-β and GSN in aging induced cardiac remodeling is still unknown. We evaluated the expressions of TGF-β and GSN in HFD fed 22 months old aging SD rats, followed by the administration of either probucol or alcalase potato protein hydrolysate (APPH). Western blotting and Masson trichrome staining showed that APPH (45 and 75 mg/kg/day) and probucol (500 mg/kg/day) treatments significantly reduced the aging and HFD-induced hypertrophy and fibrosis. Echocardiograph showed that the performance of the hearts was improved in APPH, and probucol treated HFD aging rats. Serum from all rats was collected and H9c2 cells were cultured with collected serums separately. The GSN dependent hypertrophy was inhibited with an exogenous TGF-β in H9c2 cells cultured in HFD+ APPH treated serum. Thus, we propose that along with its role in cardiac fibrosis, TGF-β also acts as an upstream activator of GSN dependent hypertrophy. Hence, TGF-β in serum could be a promising therapeutic target for cardiac remodeling in aging and/or obese subjects.
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Affiliation(s)
- Wei Syun Hu
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University, Hospital, Taichung, Taiwan
| | - Wei Jen Ting
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Shanmugam Tamilselvi
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | | | - Ting Wang
- Department of hospitality management, College of Agriculture, Tunghai University, Taichung, Taiwan
| | - Wen-Dee Chiang
- Department of Food science, College of Agriculture, Tunghai University, Taichung, Taiwan
| | | | - Yu Lan Yeh
- Department of pathology, Changhua Christian Hospital, Changhua, Taiwan
- Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | - Wan Teng Lin
- Department of hospitality management, College of Agriculture, Tunghai University, Taichung, Taiwan
| | - Chih Yang Huang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
- Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
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Mokhtari‐Zaer A, Marefati N, Atkin SL, Butler AE, Sahebkar A. The protective role of curcumin in myocardial ischemia–reperfusion injury. J Cell Physiol 2018; 234:214-222. [DOI: 10.1002/jcp.26848] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Accepted: 05/10/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Amin Mokhtari‐Zaer
- Department of Physiology School of Medicine, Mashhad University of Medical Sciences Mashhad Iran
| | - Narges Marefati
- Department of Physiology School of Medicine, Mashhad University of Medical Sciences Mashhad Iran
| | | | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute Mashhad University of Medical Sciences Mashhad Iran
- Neurogenic Inflammation Research Center Mashhad University of Medical Sciences Mashhad Iran
- School of Pharmacy Mashhad University of Medical Sciences Mashhad Iran
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Guo W, Pencina KM, Gagliano-Jucá T, Jasuja R, Morris N, O'Connell KE, Westmoreland S, Bhasin S. Effects of an ActRIIB.Fc Ligand Trap on Cardiac Function in Simian Immunodeficiency Virus-Infected Male Rhesus Macaques. J Endocr Soc 2018; 2:817-831. [PMID: 30019021 PMCID: PMC6041778 DOI: 10.1210/js.2018-00099] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 05/22/2018] [Indexed: 12/13/2022] Open
Abstract
An important safety consideration in the use of antagonists of myostatin and activins is whether these drugs induce myocardial hypertrophy and impair cardiac function. The current study evaluated the effects of a soluble ActRIIB receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-β/activin family members including myostatin, on myocardial mass and function in simian immunodeficiency virus (SIV)-infected juvenile rhesus macaques (Macaca mulatta). Fourteen pair-housed, juvenile male rhesus macaques were inoculated with SIVmac239; 4 weeks postinoculation, they were treated with weekly injections of 10 mg/kg ActRIIB.Fc or saline for 12 weeks. Myocardial mass and function were evaluated using two-dimensional echocardiography at baseline and after 12 weeks. The administration of ActRIIB.Fc was associated with a significantly greater increase in thickness of left ventricular posterior wall and interventricular septum both in diastole and systole. Cardiac output and cardiac index increased with time, more in animals treated with ActRIIB.Fc than in those treated with saline, but the difference was not statistically significant. The changes in ejection fraction, fractional shortening, and stroke volume did not differ significantly between groups. The changes in end-diastolic and end-systolic volumes did not differ between groups. In addition to a large reduction in IGF1 mRNA expression in the ActRIIB.Fc-treated animals, complex changes were detected in the myocardial expression of proteins related to calcium transport and storage. In conclusion, ActRIIB.Fc administration for 12 weeks was associated with increased myocardial mass but did not adversely affect myocardial function in juvenile SIV-infected rhesus macaques. Further studies are necessary to establish long-term cardiac safety.
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Affiliation(s)
- Wen Guo
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Karol M Pencina
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Thiago Gagliano-Jucá
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ravi Jasuja
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nancy Morris
- Division of Comparative Pathology, New England Primate Research Center, Southborough, Massachusetts
| | - Karyn E O'Connell
- Division of Comparative Pathology, New England Primate Research Center, Southborough, Massachusetts
| | - Susan Westmoreland
- Division of Comparative Pathology, New England Primate Research Center, Southborough, Massachusetts
| | - Shalender Bhasin
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Biomimetic electrical stimulation induces rat bone marrow mesenchymal stem cells to differentiate into cardiomyocyte-like cells via TGF-beta 1 in vitro. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2017; 148:47-53. [PMID: 28969971 DOI: 10.1016/j.pbiomolbio.2017.09.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/11/2017] [Accepted: 09/28/2017] [Indexed: 11/20/2022]
Abstract
Electrical conductance is one of the factors of the microenvironment of cardiomyocytes, and electrical stimulation (ES) has been shown to modulate the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) toward a cardiomyogenic fate. Transforming growth factor-beta 1 (TGF-β1) stimulates the cardiomyogenic marker expression in BMSCs. Herein, we promoted the differentiation of BMSCs into cardiomyocyte-like cells using ES to confirm if TGF-β1 mediates this event in vitro. ES increased protein levels of TGF-β1 in BMSCs, and this effect was better than that observed with 5-azacytidine (5-Aza). The effect of ES on promoting cardiomyogenic marker expression in BMSCs was enhanced by TGF-β1. Furthermore, the protein expression levels of Connexin43 (Cx43) and Alpha-actinin 2 (ACTN2) induced by ES in BMSCs were significantly decreased by pirfenidone. These results show that ES promotes cardiomyocyte-like cells differentiation in rat BMSCs and is possibly mediated by TGF-β1 in vitro.
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Cardiac Function Remains Impaired Despite Reversible Cardiac Remodeling after Acute Experimental Viral Myocarditis. J Immunol Res 2017; 2017:6590609. [PMID: 28352641 PMCID: PMC5352897 DOI: 10.1155/2017/6590609] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 12/01/2016] [Accepted: 12/15/2016] [Indexed: 12/15/2022] Open
Abstract
Background. Infection with Coxsackievirus B3 induces myocarditis. We aimed to compare the acute and chronic phases of viral myocarditis to identify the immediate effects of cardiac inflammation as well as the long-term effects after resolved inflammation on cardiac fibrosis and consequently on cardiac function. Material and Methods. We infected C57BL/6J mice with Coxsackievirus B3 and determined the hemodynamic function 7 as well as 28 days after infection. Subsequently, we analyzed viral burden and viral replication in the cardiac tissue as well as the expression of cytokines and matrix proteins. Furthermore, cardiac fibroblasts were infected with virus to investigate if viral infection alone induces profibrotic signaling. Results. Severe cardiac inflammation was determined and cardiac fibrosis was consistently colocalized with inflammation during the acute phase of myocarditis. Declined cardiac inflammation but no significantly improved hemodynamic function was observed 28 days after infection. Interestingly, cardiac fibrosis declined to basal levels as well. Both cardiac inflammation and fibrosis were reversible, whereas the hemodynamic function remains impaired after healed viral myocarditis in C57BL/6J mice.
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Ding YF, Peng YR, Shen H, Shu L, Wei YJ. Gualou Xiebai decoction inhibits cardiac dysfunction and inflammation in cardiac fibrosis rats. Altern Ther Health Med 2016; 16:49. [PMID: 26846090 PMCID: PMC4743121 DOI: 10.1186/s12906-016-1012-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 01/22/2016] [Indexed: 02/06/2023]
Abstract
Background Gualou Xiebai Decoction (GXD) is a well-known traditional Chinese recipe. It has been used to treat cardiovascular disorders for nearly two thousand years. But there is a lack of reports on cardiac fibrosis and underlying mechanism. Methods Myocardial infarction was performed by ligation of left anterior descending coronary artery (LAD) in male Wistar rats. Rats with myocardial infarction were treated with GXD (1.14 g/kg, 4.53 g/kg) daily for 4 weeks. Cardiac function was evaluated by echocardiography. Hemodynamic parameters and infarct size were measured in each group. Myocardial enzymes were examined by biochemical tests. Inflammatory cytokines were assessed by ELISA, and interrelated proteins were detected by western blot. Results Cardiac function was significantly improved in GXD-treatment rats after myocardial infarction (MI), which was accompanied with decreased infarct size. Administration of GXD to myocardial fibrosis rats significantly ameliorated the activities of AST, LDH and CK-MB in serum. The increase in inflammatory factors (TNF-α, IL-1β) were markedly reduced upon GXD treatment. Furthermore, the inflammatory mediators (NF-κB p65, TNF-α, MCP-1) were down-regulated by GXD in the myocardial fibrosis rats. Conclusions Treatment with GXD improved cardiac function induced by myocardial fibrosis by inhibiting expression of inflammatory mediators associated with NF-κB.
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Datta R, Bansal T, Rana S, Datta K, Chattopadhyay S, Chawla-Sarkar M, Sarkar S. Hsp90/Cdc37 assembly modulates TGFβ receptor-II to act as a profibrotic regulator of TGFβ signaling during cardiac hypertrophy. Cell Signal 2015; 27:2410-24. [PMID: 26362850 DOI: 10.1016/j.cellsig.2015.09.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 08/28/2015] [Accepted: 09/07/2015] [Indexed: 12/18/2022]
Abstract
Cardiac hypertrophy is accompanied by excessive collagen deposition in the heart. Despite painstaking research on this fatal disease, the precise role of molecular chaperones in myocardial fibrosis has not yet been elucidated. In this study, we have analyzed the mechanism by which Heat shock protein 90 (Hsp90)/Cell division cycle 37 (Cdc37) assembly modulates cardiac hypertrophy associated fibrosis. For the in vitro hypertrophy model, Angiotensin II (AngII) treated cultured adult cardiac fibroblasts were used, whereas the in vivo hypertrophy model was generated by renal artery ligation in adult male Wistar rats (Rattus norvegicus). Pretreatment with the Hsp90 inhibitor or the blocking of Hsp90-Cdc37 interactions during pressure overload hypertrophy resulted in ubiquitin-mediated proteasomal degradation of TGFβ receptor-II (TβR-II) leading to termination of TGFβ mediated signaling. In both cases significant reduction in collagen synthesis was observed revealing the Hsp90/Cdc37 complex as an integral profibrotic component of TGFβ signaling during cardiac hypertrophy.
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Affiliation(s)
- Ritwik Datta
- Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata-700 019, India.
| | - Trisha Bansal
- Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata-700 019, India.
| | - Santanu Rana
- Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata-700 019, India.
| | - Kaberi Datta
- Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata-700 019, India.
| | - Shiladitya Chattopadhyay
- Division of Virology, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road Scheme-XM, Beliaghata, Kolkata-700010, India.
| | - Mamta Chawla-Sarkar
- Division of Virology, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road Scheme-XM, Beliaghata, Kolkata-700010, India.
| | - Sagartirtha Sarkar
- Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata-700 019, India.
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Affiliation(s)
- Ryan A Frieler
- From Department of Molecular and Integrative Physiology (R.A.F., R.M.M.), Department of Internal Medicine, Metabolism, Endocrinology, and Diabetes Division (R.M.M.), and Department of Pharmacology (R.M.M.), University of Michigan Medical School, Ann Arbor
| | - Richard M Mortensen
- From Department of Molecular and Integrative Physiology (R.A.F., R.M.M.), Department of Internal Medicine, Metabolism, Endocrinology, and Diabetes Division (R.M.M.), and Department of Pharmacology (R.M.M.), University of Michigan Medical School, Ann Arbor.
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Yeung HM, Hung MW, Lau CF, Fung ML. Cardioprotective effects of melatonin against myocardial injuries induced by chronic intermittent hypoxia in rats. J Pineal Res 2015; 58:12-25. [PMID: 25369321 DOI: 10.1111/jpi.12190] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 10/30/2014] [Indexed: 02/06/2023]
Abstract
Obstructive sleep apnea (OSA) associated with chronic intermittent hypoxia (CIH) increases the morbidity and mortality of ischemic heart disease in patients. Yet, there is a paucity of preventive measures targeting the pathogenesis of CIH-induced myocardial injury. We examined the cardioprotective effect of melatonin against the inflammation, fibrosis and the deteriorated sarcoplasmic reticulum (SR) Ca(2+) homeostasis, and ischemia/reperfusion (I/R)-induced injury exacerbated by CIH. Adult male Sprague Dawley rats that had received a daily injection of melatonin (10 mg/kg) or vehicle were exposed to CIH treatment mimicking a severe OSA condition for 4 wk. Systolic pressure, heart weights, and malondialdehyde were significantly increased in hypoxic rats but not in the melatonin-treated group, when compared with the normoxic control. Levels of the expression of inflammatory cytokines (TNF-α, IL-6, and COX-2) and fibrotic markers (PC1 and TGF-β) were significantly elevated in the hypoxic group but were normalized by melatonin. Additionally, infarct size of isolated hearts with regional I/R was substantial in the hypoxic group treated with vehicle but not in the melatonin-treated group. Moreover, melatonin treatment mitigated the SR-Ca(2+) homeostasis in the cardiomyocyte during I/R with (i) Ca(2+) overloading, (ii) decreased SR-Ca(2+) content, (iii) lowered expression and activity of Ca(2+) -handling proteins (SERCA2a and NCX1),and (iv) decreased expressions of CAMKII and phosphorylated eNOS(ser1177). Furthermore, melatonin ameliorated the level of expression of antioxidant enzymes (CAT and MnSOD) and NADPH oxidase (p22 and NOX2). Results support a prophylactic usage of melatonin in OSA patients, which protects against CIH-induced myocardial inflammation and fibrosis with impaired SR-Ca(2+) handling and exacerbated I/R injury.
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Affiliation(s)
- Hang-Mee Yeung
- Department of Physiology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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Zhao J, Randive R, Stewart JA. Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart. World J Diabetes 2014; 5:860-867. [PMID: 25512788 PMCID: PMC4265872 DOI: 10.4239/wjd.v5.i6.860] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 09/23/2014] [Accepted: 11/03/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hyperglycemia is one of the main characteristics of diabetes. Persistent exposure to elevated glucose levels has been recognized as one of the major causal factors of diabetic complications. In pathologies, like type 2 diabetes mellitus (T2DM), mechanical and biochemical stimuli activate profibrotic signaling cascades resulting in myocardial fibrosis and subsequent impaired cardiac performance due to ventricular stiffness. High levels of glucose nonenzymatically react with long-lived proteins, such as collagen, to form advanced glycation end products (AGEs). AGE-modified collagen increase matrix stiffness making it resistant to hydrolytic turnover, resulting in an accumulation of extracellular matrix (ECM) proteins. AGEs account for many of the diabetic cardiovascular complications through their engagement of the receptor for AGE (RAGE). AGE/RAGE activation stimulates the secretion of numerous profibrotic growth factors, promotes increased collagen deposition leading to tissue fibrosis, as well as increased RAGE expression. To date, the AGE/RAGE cascade is not fully understood. In this review, we will discuss one of the major fibrotic signaling pathways, the AGE/RAGE signaling cascade, as well as propose an alternate pathway via Rap1a that may offer insight into cardiovascular ECM remodeling in T2DM. In a series of studies, we demonstrate a role for Rap1a in the regulation of fibrosis and myofibroblast differentiation in isolated diabetic and non-diabetic fibroblasts. While these studies are still in a preliminary stage, inhibiting Rap1a protein expression appears to down-regulate the molecular switch used to activate the ζ isotype of protein kinase C thereby promote AGE/RAGE-mediated fibrosis.
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Hutchinson KR, Lord CK, West TA, Stewart JA. Cardiac fibroblast-dependent extracellular matrix accumulation is associated with diastolic stiffness in type 2 diabetes. PLoS One 2013; 8:e72080. [PMID: 23991045 PMCID: PMC3749105 DOI: 10.1371/journal.pone.0072080] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 07/05/2013] [Indexed: 01/12/2023] Open
Abstract
Cardiovascular complications are a leading cause of death in patients with type 2 diabetes mellitus (T2DM). Diastolic dysfunction is one of the earliest manifestations of diabetes-induced changes in left ventricular (LV) function, and results from a reduced rate of relaxation and increased stiffness. The mechanisms responsible for increased stiffness are not completely understood. Chronic hyperglycemia, advanced glycation endproducts (AGEs), and increased levels of proinflammatory and profibrotic cytokines are molecular pathways known to be involved in regulating extracellular matrix (ECM) synthesis and accumulation resulting in increased LV diastolic stiffness. Experiments were conducted using a genetically-induced mouse model of T2DM generated by a point mutation in the leptin receptor resulting in nonfunctional leptin receptors (db/db murine model). This study correlated changes in LV ECM and stiffness with alterations in basal activation of signaling cascades and expression of profibrotic markers within primary cultures of cardiac fibroblasts from diabetic (db/db) mice with nondiabetic (db/wt) littermates as controls. Primary cultures of cardiac fibrobroblasts were maintained in 25 mM glucose (hyperglycemic-HG; diabetic db/db) media or 5 mM glucose (normoglycemic-NG, nondiabetic db/wt) media. The cells then underwent a 24-hour exposure to their opposite (NG; diabetic db/db) media or 5 mM glucose (HG, nondiabetic db/wt) media. Protein analysis demonstrated significantly increased expression of type I collagen, TIMP-2, TGF-β, PAI-1 and RAGE in diabetic db/db cells as compared to nondiabetic db/wt, independent of glucose media concentration. This pattern of protein expression was associated with increased LV collagen accumulation, myocardial stiffness and LV diastolic dysfunction. Isolated diabetic db/db fibroblasts were phenotypically distinct from nondiabetic db/wt fibroblasts and exhibited a profibrotic phenotype in normoglycemic conditions.
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Affiliation(s)
- Kirk R. Hutchinson
- Department of Physiology, University of Arizona, Tucson, Arizona, United States of America
| | - C. Kevin Lord
- Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas, United States of America
| | - T. Aaron West
- Center for Cardiovascular and Pulmonary Research, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - James A. Stewart
- Department of Biological Sciences, Mississippi State University, Starkville, Mississippi, United States of America
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Wang NP, Wang ZF, Tootle S, Philip T, Zhao ZQ. Curcumin promotes cardiac repair and ameliorates cardiac dysfunction following myocardial infarction. Br J Pharmacol 2013; 167:1550-62. [PMID: 22823335 DOI: 10.1111/j.1476-5381.2012.02109.x] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Curcumin, the natural yellow pigment extracted from the rhizomes of the plant curcuma longa, has been demonstrated to exhibit a variety of potent beneficial effects, acting as an antioxidant, anti-inflammatory and anti-fibrotic. In this study we tested the hypothesis that curcumin attenuates maladaptive cardiac repair and improves cardiac function after ischaemia and reperfusion by reducing degradation of extracellular matrix (ECM) and inhibiting synthesis of collagens via TGFβ/Smad-mediated signalling pathway. EXPERIMENTAL APPROACH Sprague-Dawley rats were subjected to 45 min of ischaemia followed by 7, 21 and 42 days of reperfusion respectively. Curcumin was fed orally at a dose of 150 mg·kg(-1) ·day(-1) only during reperfusion. KEY RESULTS Curcumin reduced the level of malondialdehyde, inhibited activity of MMPs, preserved ECM from degradation and attenuated collagen deposition, as it reduced the extent of collagen-rich scar and increased mass of viable myocardium. In addition to reducing collagen synthesis and fibrosis in the ischaemic/reperfused myocardium, curcumin significantly down-regulated the expression of TGFβ1 and phospho-Smad2/3, and up-regulated Smad7 and also increased the population of α-smooth muscle actin expressing myofibroblasts within the infarcted myocardium relative to the control. Echocardiography showed it significantly improved left ventricular end-diastolic volume, stroke volume and ejection fraction. The wall thickness of the infarcted middle anterior septum in the curcumin group was also greater than that in the control group. CONCLUSION AND IMPLICATIONS Dietary curcumin is effective at inhibiting maladaptive cardiac repair and preserving cardiac function after ischaemia and reperfusion. Curcumin has potential as a treatment for patients who have had a heart attack.
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Affiliation(s)
- Ning-Ping Wang
- Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, GA 31404, USA
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Divakaran VG, Evans S, Topkara VK, Diwan A, Burchfield J, Gao F, Dong J, Tzeng HP, Sivasubramanian N, Barger PM, Mann DL. Tumor necrosis factor receptor-associated factor 2 signaling provokes adverse cardiac remodeling in the adult mammalian heart. Circ Heart Fail 2013; 6:535-43. [PMID: 23493088 DOI: 10.1161/circheartfailure.112.000080] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Tumor necrosis factor superfamily ligands provoke a dilated cardiac phenotype signal through a common scaffolding protein termed tumor necrosis factor receptor-associated factor 2 (TRAF2); however, virtually nothing is known about TRAF2 signaling in the adult mammalian heart. METHODS AND RESULTS We generated multiple founder lines of mice with cardiac-restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (myosin heavy chain [MHC]-TRAF2(HC)). MHC-TRAF2(HC) transgenic mice developed a time-dependent increase in cardiac hypertrophy, left ventricular dilation, and adverse left ventricular remodeling, and a significant decrease in LV+dP/dt and LV-dP/dt when compared with littermate controls (P<0.05 compared with littermate). During the early phases of left ventricular remodeling, there was a significant increase in total matrix metalloproteinase activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2(HC) mice aged, there was a significant decrease in total matrix metalloproteinase activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in nuclear factor-κB activation at 4 to 12 weeks and jun N-terminal kinases activation at 4 weeks in the MHC-TRAF2(HC) mice. Transciptional profiling revealed that >95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2(HC) hearts contained κB elements in their promoters. CONCLUSIONS These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart.
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Affiliation(s)
- Vijay G Divakaran
- Winters Center for Heart Failure Research Section of Cardiology, Baylor College of Medicine, Houston, TX, USA
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Ishii R, Higashimori M, Tadakuma K, Kaneko M, Tamaki S, Sakata Y, Yamamoto K. Balloon type elasticity sensing for left ventricle of small laboratory animal. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2012; 2011:904-7. [PMID: 22254457 DOI: 10.1109/iembs.2011.6090202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
This paper describes an elasticity sensing system for left ventricle of small laboratory animal. We first show the basic concept of the proposed method, where a ring shaped specimen is dilated by a balloon type probe using a pressure based control, and the elasticity of the specimen is estimated by using the stress and strain information. We introduce a dual cylinder model for approximating the strengths of the specimen's material and the balloon. Based on this model, we can derive Young's modulus of the specimen. After explaining the developed experimental system, we show a couple of experimental results using rats and mice, where HFPEF (Heart Failure Preserved Ejection Fraction) group can be distinguished from a normal group.
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Affiliation(s)
- Ryohei Ishii
- Department of Mechanical Engineering, Osaka University, 2-1 Yamadaoka, Suita, Japan. ishii@hh
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Doyle JJ, Gerber EE, Dietz HC. Matrix-dependent perturbation of TGFβ signaling and disease. FEBS Lett 2012; 586:2003-15. [PMID: 22641039 PMCID: PMC3426037 DOI: 10.1016/j.febslet.2012.05.027] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2012] [Revised: 05/13/2012] [Accepted: 05/15/2012] [Indexed: 02/07/2023]
Abstract
Transforming growth factor beta (TGFβ) is a multipotent cytokine that is sequestered in the extracellular matrix (ECM) through interactions with a number of ECM proteins. The ECM serves to concentrate latent TGFβ at sites of intended function, to influence the bioavailability and/or function of TGFβ activators, and perhaps to regulate the intrinsic performance of cell surface effectors of TGFβ signal propagation. The downstream consequences of TGFβ signaling cascades in turn provide feedback modulation of the ECM. This review covers recent examples of how genetic mutations in constituents of the ECM or TGFβ signaling cascade result in altered ECM homeostasis, cellular performance and ultimately disease, with an emphasis on emerging therapeutic strategies that seek to capitalize on this refined mechanistic understanding.
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Filgueiras-Rama D, Castrejón S, Estrada A, Doiny D, Ortega M, Calvo C, Berenfeld O, Jalife J, Merino JL. [Basic mechanisms of the new antiarrhythmic drugs in atrial fibrillation]. ARCHIVOS DE CARDIOLOGIA DE MEXICO 2012; 82:139-152. [PMID: 22735655 PMCID: PMC5576579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023] Open
Abstract
Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. Despite of new technological breakthroughs and the understanding of the mechanisms underlying AF, based on animal models and ablation procedures in patients, the antiarrhythmic drugs remain the main therapeutic strategy to restore and maintain the sinus rhythm. New antiarrhythmic drugs are already available in the clinical practice and many others are under development. The new antiarrhythmic drugs have the capability to block atrial-specific ionic currents, which are involved in the maintenance of the arrhythmia. Parallel, increasing evidence supports the use of compounds to regulate the arrhythmogenic atrial substrate involved in the long-term maintenance of the arrhythmia (upstream therapies). This article reviews the new antiarrhythmic drugs and upstream therapies, based on the current knowledge of the mechanisms involved in the maintenance of AF.
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Affiliation(s)
- David Filgueiras-Rama
- Unidad de Arritmias y Electrofisiología Cardiaca Robotizada. Departamento de Cardiología. Hospital Universitario La Paz. Madrid. Spain
- Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan. Ann Arbor, Michigan, USA
| | - Sergio Castrejón
- Unidad de Arritmias y Electrofisiología Cardiaca Robotizada. Departamento de Cardiología. Hospital Universitario La Paz. Madrid. Spain
| | - Alejandro Estrada
- Unidad de Arritmias y Electrofisiología Cardiaca Robotizada. Departamento de Cardiología. Hospital Universitario La Paz. Madrid. Spain
| | - David Doiny
- Unidad de Arritmias y Electrofisiología Cardiaca Robotizada. Departamento de Cardiología. Hospital Universitario La Paz. Madrid. Spain
| | - Marta Ortega
- Unidad de Arritmias y Electrofisiología Cardiaca Robotizada. Departamento de Cardiología. Hospital Universitario La Paz. Madrid. Spain
| | - Conrado Calvo
- Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan. Ann Arbor, Michigan, USA
| | - Omer Berenfeld
- Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan. Ann Arbor, Michigan, USA
| | - Jose Jalife
- Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan. Ann Arbor, Michigan, USA
| | - Jose L. Merino
- Unidad de Arritmias y Electrofisiología Cardiaca Robotizada. Departamento de Cardiología. Hospital Universitario La Paz. Madrid. Spain
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Szardien S, Nef HM, Voss S, Troidl C, Liebetrau C, Hoffmann J, Rauch M, Mayer K, Kimmich K, Rolf A, Rixe J, Troidl K, Kojonazarov B, Schermuly RT, Kostin S, Elsässer A, Hamm CW, Möllmann H. Regression of cardiac hypertrophy by granulocyte colony-stimulating factor-stimulated interleukin-1β synthesis. Eur Heart J 2011; 33:595-605. [PMID: 22106340 DOI: 10.1093/eurheartj/ehr434] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
AIMS Aortic stenosis causes cardiac hypertrophy and fibrosis, which often persists despite pressure unloading after aortic valve replacement. The persistence of myocardial fibrosis in particular leads to impaired cardiac function and increased mortality. We investigated whether granulocyte colony-stimulating factor (G-CSF) beneficially influences cardiac remodelling after pressure unloading. METHODS AND RESULTS Left ventricular hypertrophy was induced by transverse aortic constriction in C57bl6 mice followed by debanding after 8 weeks. This model closely mimics aortic stenosis and subsequent aortic valve replacement. After debanding, mice were treated with either G-CSF or saline injection. Granulocyte colony-stimulating factor treatment significantly improved systolic (ejection fraction 70.48 ± 1.17 vs. 58.41 ± 1.56%, P < 0.001) and diastolic (E/E' 26.0 ± 1.0 vs. 32.6 ± 0.8, P < 0.05) function. Furthermore, cardiac fibrosis was significantly reduced in G-CSF-treated mice (collagen-I area fraction 7.96 ± 0.47 vs. 11.64 ± 1.22%, P < 0.05; collagen-III area fraction 10.73 ± 0.99 vs. 18.46 ± 0.71%, P < 0.001). Direct effects of G-CSF on cardiac fibroblasts or a relevant transdifferentiation of mobilized bone marrow cells could be excluded. However, a considerable infiltration of neutrophils was observed in G-CSF-treated mice. This sterile inflammation was accompanied by a selective release of interleukin-1 β (IL-1β) in the absence of other proinflammatory cytokines. In vitro experiments confirmed an increased expression of IL-1β in neutrophils after G-CSF treatment. Interleukin-1β directly induced the expression of the gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9 in cardiac fibroblasts thereby providing the regression of cardiac fibrosis. CONCLUSION Granulocyte colony-stimulating factor treatment improves the cardiac function and leads to the regression of myocardial fibrosis after pressure unloading. These findings reveal a previously unknown mechanism of fibrosis regression. Granulocyte colony-stimulating factor might be a potential pharmacological treatment approach for patients suffering from congestive heart failure after aortic valve replacement, although further basic research and clinical trials are required in order to prove beneficial effects of G-CSF in the human organism.
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Affiliation(s)
- Sebastian Szardien
- Department of Cardiology, Kerckhoff Heart and Thorax Center, Benekestrasse 2-8, D-61231 Bad Nauheim, Germany
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Bjørnstad JL, Skrbic B, Marstein HS, Hasic A, Sjaastad I, Louch WE, Florholmen G, Christensen G, Tønnessen T. Inhibition of SMAD2 phosphorylation preserves cardiac function during pressure overload. Cardiovasc Res 2011; 93:100-10. [DOI: 10.1093/cvr/cvr294] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Zhang W, Chancey AL, Tzeng HP, Zhou Z, Lavine KJ, Gao F, Sivasubramanian N, Barger PM, Mann DL. The development of myocardial fibrosis in transgenic mice with targeted overexpression of tumor necrosis factor requires mast cell-fibroblast interactions. Circulation 2011; 124:2106-16. [PMID: 22025605 DOI: 10.1161/circulationaha.111.052399] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF mice) develop progressive myocardial fibrosis, diastolic dysfunction, and adverse cardiac remodeling. Insofar as tumor necrosis factor (TNF) does not directly stimulate fibroblast collagen synthesis, we asked whether TNF-induced fibrosis was mediated indirectly through interactions between mast cells and cardiac fibroblasts. METHODS AND RESULTS Cardiac mast cell number increased 2 to 3 fold (P<0.001) in MHCsTNF mice compared with littermate controls. Outcrossing MHCsTNF mice with mast cell-deficient (c-kit(-/-)) mice showed that the 11-fold increase (P<0.001) in collagen volume fraction in MHCsTNF/c-kit(+/-) mice was abrogated in MHCsTNF/c-kit(-/-) mice, and that the leftward shifted left ventricular pressure-volume curve in the MHCsTNF/c-kit(+/-) mice was normalized in the MHCsTNF/c-kit(-/-) hearts. Furthermore, the increase in transforming growth factor β1 and type I transforming growth factor β receptor messenger RNA levels was significantly (P=0.03, P=0.01, respectively) attenuated in MHCsTNF/c-kit(-/-) when compared with MHCsTNF/c-kit(+/-) mice. Coculture of fibroblasts with mast cells resulted in enhanced α-smooth muscle actin expression, increased proliferation and collagen messenger RNA expression, and increased contraction of 3-dimensional collagen gels in MHCsTNF fibroblasts compared with littermate fibroblasts. The effects of mast cells were abrogated by type I transforming growth factor β receptor antagonist NP-40208. CONCLUSIONS These results suggest that increased mast cell density with resultant mast cell-cardiac fibroblast cross-talk is required for the development of myocardial fibrosis in inflammatory cardiomyopathy. Cardiac fibroblasts exposed to sustained inflammatory signaling exhibit an increased repertoire of profibrotic phenotypic responses in response to mast cell mediators.
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Affiliation(s)
- Weili Zhang
- Division of Cardiology, Washington University School of Medicine, 660 S Euclid Avenue, St. Louis, MO 63110, USA.
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Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-β signaling in cardiac remodeling. J Mol Cell Cardiol 2011; 51:600-6. [PMID: 21059352 PMCID: PMC3072437 DOI: 10.1016/j.yjmcc.2010.10.033] [Citation(s) in RCA: 737] [Impact Index Per Article: 52.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 10/28/2010] [Accepted: 10/29/2010] [Indexed: 12/12/2022]
Abstract
Myocardial TGF-β expression is upregulated in experimental models of myocardial infarction and cardiac hypertrophy, and in patients with dilated or hypertrophic cardiomyopathy. Through its effects on cardiomyocytes, mesenchymal and immune cells, TGF-β plays an important role in the pathogenesis of cardiac remodeling and fibrosis. TGF-β overexpression in the mouse heart is associated with fibrosis and hypertrophy. Endogenous TGF-β plays an important role in the pathogenesis of cardiac fibrotic and hypertrophic remodeling, and modulates matrix metabolism in the pressure-overloaded heart. In the infarcted heart, TGF-β deactivates inflammatory macrophages, while promoting myofibroblast transdifferentiation and matrix synthesis through Smad3-dependent pathways. Thus, TGF-β may serve as the "master switchThis article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure". for the transition of the infarct from the inflammatory phase to formation of the scar. Because of its crucial role in cardiac remodeling, the TGF-β system may be a promising therapeutic target for patients with heart failure. However, efforts to translate these concepts into therapeutic strategies, in order to prevent cardiac hypertrophy and fibrosis, are hampered by the complex, pleiotropic and diverse effects of TGF-β signaling, by concerns regarding deleterious actions of TGF-β inhibition and by the possibility of limited benefit in patients receiving optimal treatment with ACE inhibitors and β-adrenergic blockers. Dissection of the pathways responsible for specific TGF-β-mediated actions and understanding of cell-specific actions of TGF-β are needed to design optimal therapeutic strategies. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure".
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Affiliation(s)
- Marcin Dobaczewski
- Division of Cardiology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA
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Tong W, Zhang L. Fetal hypoxia and programming of matrix metalloproteinases. Drug Discov Today 2011; 17:124-34. [PMID: 21946060 DOI: 10.1016/j.drudis.2011.09.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Revised: 06/15/2011] [Accepted: 09/14/2011] [Indexed: 12/17/2022]
Abstract
Fetal hypoxia adversely affects the brain and heart development, yet the mechanisms responsible remain elusive. Recent studies indicate an important role of the extracellular matrix in fetal development and tissue remodeling. The matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs) have been implicated in a variety of physiological and pathological processes in the cardiovascular and central nervous systems. This review summarizes current knowledge of the mechanisms by which fetal hypoxia induces the imbalance of MMPs, TIMPs and collagen expression patterns, resulting in growth restriction and aberrant tissue remodeling in the developing heart and brain. Collectively, this information could lead to the development of preventive diagnoses and therapeutic strategies in the fetal programming of cardiovascular and neurological disorders.
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Affiliation(s)
- Wenni Tong
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
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Lenski M, Kazakov A, Marx N, Böhm M, Laufs U. Effects of DPP-4 inhibition on cardiac metabolism and function in mice. J Mol Cell Cardiol 2011; 51:906-18. [PMID: 21871459 DOI: 10.1016/j.yjmcc.2011.08.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Revised: 06/27/2011] [Accepted: 08/05/2011] [Indexed: 01/13/2023]
Abstract
Type 2 diabetes is associated with an increased risk of cardiac complications. Inhibitors of dipeptidylpeptidase 4 (DPP-4) are novel drugs for the treatment of patients with type 2 diabetes. The effect of DPP-4 inhibitors on myocardial metabolism has not been studied in detail. In wild-type C57Bl6-mice, 3weeks of treatment with sitagliptin had no effect on body weight and glucose tolerance nor on phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoAcarboxylase (ACC), phosphofructokinase-2 (PFK2) or tuberin-2 (TSC2) in the left ventricular myocardium. However, in 10week old db/db-/- mice, a model of diabetes and obesity, sitagliptin potently reduced plasma glucose rise in peritoneal glucose tolerance tests and reduced weight increase. The myocardium of untreated db/db-/- mice exhibited a marked increase of the phosphorylation of AMPK, ACC, TSC2, expression of p53 and fatty acid translocase (FAT/CD36) membrane expression. These changes were reduced by DPP-4 inhibition. Sitagliptin showed no effect on cardiomyocyte size but prevented myocardial fibrosis in the 10week old db/db-/- mice and reduced expression of TGF-β1, markers of oxidative stress and the accumulation of advanced glycation end products in cardiomyocytes. Working heart analyses did not show an effect of sitagliptin on parameters of systolic cardiac function. In animals with diabetes and obesity, sitagliptin improved glucose tolerance, reduced weight gain, myocardial fibrosis and oxidative stress. Furthermore the study provides evidence that treatment with sitagliptin decreases elevated myocardial fatty acid uptake and oxidation in the diabetic heart. These observations show beneficial myocardial metabolic effect of DPP-4 inhibition in this mouse model of diabetes and obesity.
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Affiliation(s)
- M Lenski
- Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
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Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA. Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload. J Clin Invest 2011; 121:2301-12. [PMID: 21537080 DOI: 10.1172/jci44824] [Citation(s) in RCA: 288] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 03/02/2011] [Indexed: 01/05/2023] Open
Abstract
The cardiac pathological response to sustained pressure overload involves myocyte hypertrophy and dysfunction along with interstitial changes such as fibrosis and reduced capillary density. These changes are orchestrated by mechanical forces and factors secreted between cells. One such secreted factor is TGF-β, which is generated by and interacts with multiple cell types. Here we have shown that TGF-β suppression in cardiomyocytes was required to protect against maladaptive remodeling and involved noncanonical (non-Smad-related) signaling. Mouse hearts subjected to pressure overload and treated with a TGF-β-neutralizing Ab had suppressed Smad activation in the interstitium but not in myocytes, and noncanonical (TGF-β-activated kinase 1 [TAK1]) activation remained. Although fibrosis was greatly reduced, chamber dysfunction and dilation persisted. Induced myocyte knockdown of TGF-β type 2 receptor (TβR2) blocked all maladaptive responses, inhibiting myocyte and interstitial Smad and TAK1. Myocyte knockdown of TβR1 suppressed myocyte but not interstitial Smad, nor TAK1, modestly reducing fibrosis without improving chamber function or hypertrophy. Only TβR2 knockdown preserved capillary density after pressure overload, enhancing BMP7, a regulator of the endothelial-mesenchymal transition. BMP7 enhancement also was coupled to TAK1 suppression. Thus, myocyte targeting is required to modulate TGF-β in hearts subjected to pressure overload, with noncanonical pathways predominantly affecting the maladaptive hypertrophy/dysfunction.
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Affiliation(s)
- Norimichi Koitabashi
- Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA
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Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. Basic Res Cardiol 2011; 106:801-14. [DOI: 10.1007/s00395-011-0184-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Revised: 03/07/2011] [Accepted: 04/20/2011] [Indexed: 01/17/2023]
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In vitro epithelial-to-mesenchymal transformation in human adult epicardial cells is regulated by TGFβ-signaling and WT1. Basic Res Cardiol 2011; 106:829-47. [PMID: 21516490 PMCID: PMC3149675 DOI: 10.1007/s00395-011-0181-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Revised: 03/25/2011] [Accepted: 04/07/2011] [Indexed: 11/16/2022]
Abstract
Adult epicardial cells are required for endogenous cardiac repair. After myocardial injury, they are reactivated, undergo epithelial-to-mesenchymal transformation (EMT) and migrate into the injured myocardium where they generate various cell types, including coronary smooth muscle cells and cardiac interstitial fibroblasts, which contribute to cardiac repair. To understand what drives epicardial EMT, we used an in vitro model for human adult epicardial cells. These cells have an epithelium-like morphology and markedly express the cell surface marker vascular cell adhesion marker (VCAM-1). In culture, epicardial cells spontaneously undergo EMT after which the spindle-shaped cells now express endoglin. Both epicardial cells before and after EMT express the epicardial marker, Wilms tumor 1 (WT1). Adding transforming growth factor beta (TGFβ) induces loss of epithelial character and initiates the onset of mesenchymal differentiation in human adult epicardial cells. In this study, we show that TGFβ-induced EMT is dependent on type-1 TGFβ receptor activity and can be inhibited by soluble VCAM-1. We also show that epicardial-specific knockdown of Wilms tumor-1 (WT1) induces the process of EMT in human adult epicardial cells, through transcriptional regulation of platelet-derived growth factor receptor alpha (Pdgfrα), Snai1 and VCAM-1. These data provide new insights into the process of EMT in human adult epicardial cells, which might provide opportunities to develop new strategies for endogenous cell-based cardiac repair.
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Abstract
The cytokine hypothesis presently suggests that an excessive production of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF) and interleukin 6 (IL6), contributes to the pathogenesis of heart failure. The concept, successfully proved in genetically modified animal models, failed to translate to humans. Recently, accumulation of apparently paradoxical experimental data demonstrates that, under certain conditions, production of pro-inflammatory cytokines can initiate the activation of a pro-survival cardioprotective signalling pathway. This novel path that involves the activation of a transcription factor, signal transducer and activator of transcription 3 (STAT3), has been termed the survival activating factor enhancement (SAFE) pathway. In this review, we will discuss whether targeting the SAFE pathway may be considered as a preventive and/or therapeutic measure for the treatment of heart failure.
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Affiliation(s)
- Sandrine Lecour
- Hatter Cardiovascular Research Institute, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
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49
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Deficiency in TIMP-3 increases cardiac rupture and mortality post-myocardial infarction via EGFR signaling: beneficial effects of cetuximab. Basic Res Cardiol 2011; 106:459-71. [PMID: 21243368 DOI: 10.1007/s00395-010-0147-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2010] [Revised: 11/29/2010] [Accepted: 12/23/2010] [Indexed: 12/17/2022]
Abstract
Cardiac rupture is a fatal complication of myocardial infarction (MI); however, its underlying molecular mechanisms are not fully understood. This study investigated the role of tissue inhibitor of metalloproteinase-3 (TIMP-3)/matrix metalloproteinase (MMP)/epidermal growth factor (EGF)/transforming growth factor (TGF)-β1 pathway in infarct healing and effects of cetuximab on cardiac rupture after MI. Induction of MI was achieved by left coronary artery ligation in wild-type (WT) and TIMP-3(-/-) mice. TIMP-3 deficiency resulted in a fourfold increase in cardiac rupture and 50% decrease in survival after MI. Hydroxyproline content, collagen synthesis and myofibroblast cell number in the infarct region, and the force required to induce rupture of the infarct scar were significantly decreased, while MMP activity was increased in TIMP-3(-/-) mice. EGF proteins were increased by threefold in TIMP-3(-/-) mice following MI, while TGF-β1 mRNA levels were decreased by 68%. Cell proliferation of cultured adult cardiac myofibroblasts was significantly decreased in TIMP-3(-/-) compared to WT myofibroblasts. EGF treatment significantly decreased collagen synthesis and TGF-β1 expression. Conversely, TGF-β1 treatment increased collagen synthesis in cardiac myofibroblasts. Treatment with cetuximab significantly decreased the incidence of cardiac rupture and improved survival post-MI in TIMP-3(-/-) mice. We conclude that deficiency in TIMP-3 increases cardiac rupture post-MI via EGF/epidermal growth factor receptor (EGFR) signaling which downregulates TGF-β1 expression and collagen synthesis. Inhibition of EGFR by cetuximab protects against cardiac rupture and improves survival post-MI.
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50
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Cieslik KA, Taffet GE, Carlson S, Hermosillo J, Trial J, Entman ML. Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart. J Mol Cell Cardiol 2011; 50:248-56. [PMID: 20974150 PMCID: PMC3019252 DOI: 10.1016/j.yjmcc.2010.10.019] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 10/15/2010] [Indexed: 12/16/2022]
Abstract
Diastolic dysfunction in the aging heart is a grave condition that challenges the life and lifestyle of a growing segment of our population. This report seeks to examine the role and interrelationship of inflammatory dysregulation in interstitial myocardial fibrosis and progressive diastolic dysfunction in aging mice. We studied a population of C57BL/6 mice that developed progressive diastolic dysfunction over 30 months of life. This progressive dysfunction was associated with increasing infiltration of CD45(+) fibroblasts of myeloid origin. In addition, increased rates of collagen expression as measured by cellular procollagen were apparent in the heart as a function of age. These cellular and functional changes were associated with progressive increases in mRNA for MCP-1 and IL-13, which correlated both temporally and quantitatively with changes in fibrosis and cellular procollagen levels. MCP-1 protein was also increased and found to be primarily in the venular endothelium. Protein assays also demonstrated elevation of IL-4 and IL-13 suggesting a shift to a Th2 phenotype in the aging heart. In vitro studies demonstrated that IL-13 markedly enhanced monocyte-fibroblast transformation. Our results indicate that immunoinflammatory dysregulation in the aging heart induces progressive MCP-1 production and an increased shift to a Th2 phenotype paralleled by an associated increase in myocardial interstitial fibrosis, cellular collagen synthesis, and increased numbers of CD45(+) myeloid-derived fibroblasts that contain procollagen. The temporal association and functional correlations suggest a causative relationship between age-dependent immunoinflammatory dysfunction, fibrosis and diastolic dysfunction.
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Affiliation(s)
- Katarzyna A Cieslik
- Baylor College of Medicine, One Baylor Plaza, M.S. BCM620, Houston, TX 77030, USA.
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