The Center of Cardiovascular Diseases, the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, China.
Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzhen, 518057, China.
J Bioenerg Biomembr. 2020 Jun;52(3):155-164. doi: 10.1007/s10863-020-09832-w. Epub 2020 Apr 14.
Myocardial infarction represents one of the severe cardiovascular diseases and is one of the high-risk factors for mortality, and ischemia/reperfusion (I/R) injury is one of the risk factors that contribute to the high mortality of myocardial infarction. MicroRNAs have been proven as key regulators in various diseases including myocardial infarction. The present study was sought to determine the role of miR-703 in the myocardial I/R injury and to explore detailed mechanisms. Hypoxia/reoxygenation (H/R) treatment repressed cell viability, increased cytotoxicity and pyroptosis in mouse cardiomyocytes. More importantly, we found that miR-703 was suppressed in mouse cardiomyocytes upon H/R stimulation. Restoration of miR-703 expression in mouse cardiomyocytes counteracted the H/R-induced cytotoxicity and pyroptosis in mouse cardiomyocytes; and the effects of miR-703 inhibition on cell viability and pyroptosis were similar to that of H/R treatment in mouse cardiomyocytes. In a further investigation, we found that NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) was targeted and repressed by miR-703 in mouse cardiomyocytes. NLRP3 knockdown also attenuated H/R-induced cytotoxicity and pyroptosis in mouse cardiomyocytes. In the mechanistic perspective, NLRP3 enforced expression disrupted the protective effects of miR-703 restoration on the H/R-induced cytotoxicity and pyroptosis in mouse cardiomyocytes. Our results for the first time demonstrate the protective actions of miR-703 in the H/R-induced mouse cardiomyocyte injury. More importantly, miR-703 protects against H/R-induced cardiomyocyte injury via inhibiting the NLRP3/caspase-1-mediated pyroptosis.
心肌梗死是一种严重的心血管疾病，也是导致死亡率高的危险因素之一，而缺血/再灌注（I/R）损伤是导致心肌梗死死亡率高的危险因素之一。microRNAs 已被证明是包括心肌梗死在内的各种疾病的关键调节因子。本研究旨在确定 miR-703 在心肌 I/R 损伤中的作用，并探讨其详细机制。缺氧/复氧（H/R）处理抑制了小鼠心肌细胞的活力，增加了其细胞毒性和细胞焦亡。更重要的是，我们发现 H/R 刺激可抑制小鼠心肌细胞中 miR-703 的表达。在小鼠心肌细胞中恢复 miR-703 的表达可逆转 H/R 诱导的小鼠心肌细胞的细胞毒性和细胞焦亡；并且 miR-703 抑制对细胞活力和细胞焦亡的作用与 H/R 处理在小鼠心肌细胞中的作用相似。在进一步的研究中，我们发现 NOD、LRR 和 pyrin 结构域蛋白 3（NLRP3）是 miR-703 在小鼠心肌细胞中的靶基因，并受到其抑制。NLRP3 的敲低也可减轻 H/R 诱导的小鼠心肌细胞的细胞毒性和细胞焦亡。从机制上讲，NLRP3 的强制表达破坏了 miR-703 恢复对 H/R 诱导的小鼠心肌细胞毒性和细胞焦亡的保护作用。我们的研究结果首次证明了 miR-703 在 H/R 诱导的小鼠心肌细胞损伤中的保护作用。更重要的是，miR-703 通过抑制 NLRP3/caspase-1 介导的细胞焦亡来保护 H/R 诱导的心肌细胞损伤。
