Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Int J Mol Med. 2013 Nov;32(5):1011-20. doi: 10.3892/ijmm.2013.1475. Epub 2013 Aug 27.
Myocardial ischemia/reperfusion (MI/R) leads to oxidative stress, which may in turn lead to myocardial injury. In the present study, we investigated the effects of exenatide, a glucagon-like peptide-1 (GLP-1) analogue, on oxidative stress-induced injury in vitro and in vivo. In in vitro experiments, H9c2 cells were incubated with exenatide to determine the direct cytoprotective effects of exenatide following exposure to hydrogen peroxide (H2O2). Pre-treatment with exenatide (1 nM), prior to H2O2 exposure, increased cell viability and inhibited H2O2-induced reactive oxygen species (ROS) production. Exenatide also decreased the levels of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the cultured supernatants, as well as those of malondialdehyde (MDA) in the H9c2 cells and increased the total superoxide dismutase (T-SOD) levels in the H9c2 cells. In in vivo experiments, an animal model of MI/R was induced by coronary occlusion. Pre-treatment with exenatide (10 µg/kg/day) protected the rat hearts from MI/R-induced injury by decreasing the levels of LDH and CK-MB in plasma, increasing the levels of catalase, T-SOD and glutathione peroxidase (GSH-Px) in the heart and decreasing the MDA levels in the rats with MI/R-induced injury. Exenatide also reduced the infarct size and enhanced cardiac function in the rats with MI/R-induced injury. Moreover, pre-treatment with exenatide inhibited cardiomyocyte apoptosis, increased Aktserine473 and Badserine136 phosphorylation and decreased cleaved caspase-3 expression in vitro and in vivo; however, these effects were attenuated by the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Our results suggest that exenatide exerts significant cardioprotective effects against oxidative stress-induced injury in vitro and in vivo. The mechanisms involved may be attributed to the scavenging of oxidative stress products, such as ROS, the increase in the concentrations of antioxidant defense enzymes and the inhibition of cardiomyocyte apoptosis. The anti-apoptotic effects of exenatide were, at least in part, associated with the activation of the PI3K/Akt signaling pathway.
心肌缺血/再灌注（MI/R）导致氧化应激，进而导致心肌损伤。在本研究中，我们研究了 exenatide（一种胰高血糖素样肽-1（GLP-1）类似物）对体外和体内氧化应激诱导损伤的影响。在体外实验中，将 H9c2 细胞与 exenatide 孵育，以确定 exenatide 在暴露于过氧化氢（H2O2）后对细胞的直接保护作用。在暴露于 H2O2 之前，用 1 nM 的 exenatide 预处理可增加细胞活力并抑制 H2O2 诱导的活性氧（ROS）的产生。exenatide 还降低了培养上清液中乳酸脱氢酶（LDH）和肌酸激酶同工酶-MB（CK-MB）的水平，以及 H9c2 细胞中丙二醛（MDA）的水平，并增加了 H9c2 细胞中的总超氧化物歧化酶（T-SOD）水平。在体内实验中，通过冠状动脉闭塞诱导 MI/R 动物模型。用 exenatide（10 µg/kg/天）预处理可通过降低血浆中 LDH 和 CK-MB 的水平、增加心脏中过氧化氢酶、T-SOD 和谷胱甘肽过氧化物酶（GSH-Px）的水平以及降低 MDA 的水平来保护大鼠免受 MI/R 诱导的损伤。exenatide 还减少了 MI/R 诱导损伤大鼠的梗塞面积并增强了心脏功能。此外，用 exenatide 预处理可抑制体外和体内的心肌细胞凋亡，增加 Akt 丝氨酸 473 和 Bad 丝氨酸 136 的磷酸化，并降低 cleaved caspase-3 的表达；然而，这些作用被磷脂酰肌醇 3-激酶（PI3K）抑制剂 LY294002 减弱。我们的结果表明，exenatide 对体外和体内氧化应激诱导的损伤具有显著的心脏保护作用。涉及的机制可能归因于清除氧化应激产物，如 ROS，增加抗氧化防御酶的浓度和抑制心肌细胞凋亡。exenatide 的抗凋亡作用至少部分与激活 PI3K/Akt 信号通路有关。
