Exendin-4 inhibits structural remodeling and improves Ca2+ homeostasis in rats with heart failure via the GLP-1 receptor through the eNOS/cGMP/PKG pathway |
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| Institution: | 1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China;2. Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China;3. Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan 430060, China;1. Department of Geriatrics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China;2. Department of Geriatrics, The Second Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing, 400010, China;1. Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan;2. Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan;3. Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan;1. Institute of Cardiovascular Science, Beijing, 100191, China;2. Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China;1. School of Pharmaceutical Sciences Geneva-Lausanne, University of Geneva, University of Lausanne, Geneva, Switzerland;2. Department of Cell Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland;3. Department of Radiology, Geneva University Hospital, Geneva, Switzerland;4. Sanofi Germany, Industriepark Höchst, Frankfurt, Germany |
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| Abstract: | The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 is a long-acting analog of GLP-1, which stimulates insulin secretion and is clinically used in the treatment of type 2 diabetes. Previous studies have demonstrated that GLP-1 agonists and analogs serve as cardioprotective factors in various conditions. Disturbances in calcium cycling are characteristic of heart failure (HF); therefore, the aim of this study was to investigate the effect of exendin-4 (a GLP-1 mimetic) on the regulation of calcium handling and to identify the underlying mechanisms in an HF rat model after myocardial infarction (MI). Rats underwent surgical ligation of the left anterior descending coronary artery or sham surgery prior to infusion with vehicle, exendin-4, or exendin-4 and exendin9-39 for 4 weeks. Exendin-4 treatment decreased MI size, suppressed chamber dilation, myocyte hypertrophy, and fibrosis and improved in vivo heart function in the rats subjected to MI. Exendin-4 resulted in an increase in circulating GLP-1 and GLP-1R in ventricular tissues. Additionally, exendin-4 activated the eNOS/cGMP/PKG signaling pathway and inhibited the Ca2+/calmodulin-dependent kinase II (CaMKII) pathways. Myocytes isolated from exendin-4-treated hearts displayed higher Ca2+ transients, higher sarcoplasmic reticulum Ca2+ content, and higher l-type Ca2+ current densities than MI hearts. Exendin-4 treatment restored the protein expression of sarcoplasmic reticulum Ca2+ uptake ATPase (SERCA2a), phosphorylated phospholamban (PLB) and Cav1.2 and decreased the levels of phosphorylated ryanodine receptor (RyR). Moreover, the favorable effects of exendin-4 were significantly inhibited by exendin9-39 (a GLP-1 receptor antagonist). Exendin-4 treatment of an HF rat model after MI inhibited cardiac and cardiomyocytes progressive remodeling. In addition, Ca2+ handling and its molecular modulation were also improved by exendin-4 treatment. The beneficial effects of exendin-4 on cardiac remodeling may be mediated through activation of the eNOS/cGMP/PKG pathway. |
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| Keywords: | Exendin-4 Heart Failure Calmodulin-Dependent Kinase II eNOS/cGMP/PKG Pathway Calcium Handing |
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