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
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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DOI：
10.1016/j.peptides.2017.02.008
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发表时间：
2017-04-01
期刊：
影响因子：
3
通讯作者：
Huang, Congxin
中科院分区：
文献类型：
--
作者：
Chen, Jingjing;Wang, Dandan;Huang, Congxin
胰高血糖素样肽-1受体（GLP-1 R）激动剂exendin-4是GLP-1的长效类似物，可刺激胰岛素分泌，临床上用于治疗2型糖尿病。先前的研究已经证明GLP-1激动剂和类似物在各种条件下作为心脏保护因子。钙循环紊乱是心力衰竭（HF）的特征;因此，本研究的目的是研究exendin-4（GLP-1模拟物）对钙处理调节的影响，并确定心肌梗死（MI）后HF大鼠模型的潜在机制。在用载体、毒蜥外泌肽-4或毒蜥外泌肽-4和9 -39输注4周之前，对大鼠进行左前降支冠状动脉的手术结扎或假手术。Exendin-4治疗减少MI大小，抑制心室扩张、肌细胞肥大和纤维化，并改善MI大鼠的体内心脏功能。Exendin-4导致心室组织中循环GLP-1和GLP-1 R增加。此外，exendin-4激活eNOS/cGMP/PKG信号通路并抑制Ca 2 +/钙调蛋白依赖性激酶II（CaMKII）通路。从exendin-4处理的心脏中分离的心肌细胞显示出比MI心脏更高的Ca 2+瞬变、更高的肌浆网Ca 2+含量和更高的L型Ca 2+电流密度。Exendin-4处理恢复了肌浆网Ca 2+摄取ATP酶（SERCA 2a）、磷酸化受磷蛋白（PLB）和Cav1.2的蛋白表达，降低了磷酸化兰尼碱受体（RyR）的水平。此外，exendin-4的有利作用被exendin 9 -39（GLP-1受体拮抗剂）显著抑制。Exendin-4治疗MI后的HF大鼠模型抑制心脏和心肌细胞进行性重塑。此外，Ca 2+处理和其分子调节也通过exendin-4处理得到改善。exendin-4对心脏重塑的有益作用可能通过激活eNOS/cGMP/PKG通路介导。(C)2017爱思唯尔公司All rights reserved.
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. (C) 2017 Elsevier Inc. All rights reserved.