Cai Huaiqiu, Zhang Gaigai, Chen Wenjia, Zhang Bo, Zhang Jinsheng, Chang Jinrui, Tang Chaoshu, Qi Yongfen, Yin Xinhua
Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Geriatrics and Gerontology, Beijing Huaxin Hospital, the First Affiliated Hospital of Tsinghua University, Beijing, China.
Pharmazie. 2014 Jan;69(1):64-9.
Clinical studies have suggested that metformin, a widely used antidiabetic agent, exerts a direct cardioprotective effect on cardiovascular disease in addition to its blood glucose-lowering activity. This study was designed to identify the role of metformin in rats with isoproterenol (ISO)-induced myocardial injury and to investigate its underlying mechanism. A rat model of myocardial ischemic injury was established by the subcutaneous injection of a high dose of ISO, a beta-adrenergic agonist. The results showed that pretreatment of metformin significantly reduced rat mortality induced by ISO, attenuated the increased plasma lactate dehydrogenase activity and myocardium malondialdehyde level, alleviated the hemodynamic disturbance, inhibited the upregulated gene expression of myocardial probrain natriuretic peptide and alleviated the myocardial morphological injury and apoptosis induced by ISO. Furthermore, western blot analysis showed that metformin suppressed the overexpression of the endoplasmic reticulum stress (ERS) markers cleaved caspase-12 and CEBP-homologous protein induced by ISO and increased the phosphorylation of AMP-activated protein kinase (AMPK). In conclusion, these data suggest that metformin might protect the myocardium against acute ischemic injury in rats at least partially by activating AMPK and alleviating aberrant ERS. These findings might provide further experimental evidence for treating patients at risk of ischemic heart disease with metformin.
临床研究表明，二甲双胍作为一种广泛使用的抗糖尿病药物，除了具有降血糖活性外，还对心血管疾病具有直接的心脏保护作用。本研究旨在确定二甲双胍在异丙肾上腺素（ISO）诱导的大鼠心肌损伤中的作用，并探讨其潜在机制。通过皮下注射高剂量的β-肾上腺素能激动剂ISO建立大鼠心肌缺血损伤模型。结果表明，二甲双胍预处理显著降低了ISO诱导的大鼠死亡率，减轻了血浆乳酸脱氢酶活性升高和心肌丙二醛水平，缓解了血流动力学紊乱，抑制了心肌脑钠肽基因表达上调，并减轻了ISO诱导的心肌形态学损伤和细胞凋亡。此外，蛋白质印迹分析表明，二甲双胍抑制了ISO诱导的内质网应激（ERS）标志物半胱天冬酶-12和CEBP同源蛋白的过表达，并增加了AMP活化蛋白激酶（AMPK）的磷酸化。总之，这些数据表明，二甲双胍可能至少部分通过激活AMPK和减轻异常的ERS来保护大鼠心肌免受急性缺血损伤。这些发现可能为用二甲双胍治疗缺血性心脏病风险患者提供进一步的实验证据。
