Metformin protects against myocardial ischemia-reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway

作者：Jing Zhang, Lelin Huang, Xingming Shi, Liu Yang, Fuzhou Hua, Jianyong Ma, Wengen Zhu, Xiao Liu, Rui Xuan, Yunfeng Shen, Jianping Liu, Xiaoyang Lai, Peng Yu · 发表于：Aging · 年份：2020 · DOI：10.18632/aging.202143 · 被引用次数：273 · 研究领域：Autophagy in Disease and Therapy、Mitochondrial Function and Pathology、Inflammasome and immune disorders

Ischemia/reperfusion (I/R) injury is a life-threatening vascular emergency following myocardial infarction. Our previous study showed cardioprotective effects of metformin against myocardial I/R injury. In this study, we further examined the involvement of AMPK mediated activation of NLRP3 inflammasome in this cardioprotective effect of metformin. Myocardial I/R injury was simulated in a rat heart Langendorff model and neonatal rat ventricle myocytes (NRVMs) were subjected to hypoxi/reoxygenation (H/R) to establish an in vitro model. Outcome measures included myocardial infarct size, hemodynamic monitoring, myocardial tissue injury, myocardial apoptotic index and the inflammatory response. myocardial infarct size and cardiac enzyme activities. First, we found that metformin postconditioning can not only significantly alleviated myocardial infarct size, attenuated cell apoptosis, and inhibited myocardial fibrosis. Furthermore, metformin activated phosphorylated AMPK, decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and decreased NLRP3 inflammasome activation. In isolated NRVMs metformin increased cellular viability, decreased LDH activity and inhibited cellular apoptosis and inflammation. Importantly, inhibition of AMPK phosphorylation by Compound C (CC) resulted in decreased survival of cardiomyocytes mainly by inducing the release of inflammatory cytokines and increasing NLRP3 inflammasome activation. Finally, in vitro studies revealed that the NLRP3 activator ni...