Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
Emergency Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
Oxid Med Cell Longev. 2021 Jul 27;2021:6366254. doi: 10.1155/2021/6366254. eCollection 2021.
Evidence suggests that miR-146a is implicated in the pathogenesis of cardiovascular diseases; however, the role of miR-146a in myocardial ischaemia reperfusion (I/R) injury is unclear. The aim of this study was to explore the functional role of miR-146a in myocardial ischaemia reperfusion injury and the underlying mechanism. C57BL/6J mice were subjected to 45 min of ischaemia and 1 week of reperfusion to establish a myocardial I/R injury model. A miR-146a mimic (0.5 mg/kg) was administered intravenously at the beginning of the ischaemia process. Neonatal rat cardiomyocytes were also subjected to hypoxia/reperfusion (H/R). Cells were treated with the miR-146a mimic or antagonist. As a result, the miR-146a mimic attenuated H/R-induced cardiomyocyte injury, as evidenced by increased cell viability and reduced lactate dehydrogenase (LDH) levels. In addition, the miR-146a mimic inhibited oxidative stress in cells suffering from H/R injury. Moreover, the miR-146a antagonist exerted adverse effects in vitro. In mice with myocardial I/R injury, the miR-146a mimic preserved cardiac function and reduced the infarction area and fibrosis. Moreover, the miR-146a mimic decreased the inflammatory response and reactive oxygen species (ROS) accumulation in mouse hearts. Mechanistically, we found that miR-146a directly regulated the transcription of NOX4, which subsequently affected P38 signalling in cardiomyocytes. When we knocked down NOX4, the effects of the miR-146a antagonist in worsening the cell condition were counteracted in in vitro experiments. Taken together, the results suggest that miR-146a protects against myocardial ischaemia reperfusion injury by inhibiting NOX4 signalling. The miR-146a mimic may become a potential therapeutic approach for patients with myocardial ischaemia reperfusion.
有证据表明，miR-146a 参与了心血管疾病的发病机制；然而，miR-146a 在心肌缺血再灌注（I/R）损伤中的作用尚不清楚。本研究旨在探讨 miR-146a 在心肌缺血再灌注损伤中的功能作用及其潜在机制。C57BL/6J 小鼠接受 45 分钟缺血和 1 周再灌注，建立心肌 I/R 损伤模型。在缺血过程开始时，静脉注射 miR-146a 模拟物（0.5mg/kg）。新生大鼠心肌细胞也经历缺氧/复氧（H/R）。用 miR-146a 模拟物或拮抗剂处理细胞。结果表明，miR-146a 模拟物减轻了 H/R 诱导的心肌细胞损伤，表现为细胞活力增加和乳酸脱氢酶（LDH）水平降低。此外，miR-146a 模拟物抑制了 H/R 损伤细胞中的氧化应激。此外，miR-146a 拮抗剂在体外产生了不良影响。在心肌 I/R 损伤的小鼠中，miR-146a 模拟物保存了心脏功能，减少了梗塞面积和纤维化。此外，miR-146a 模拟物减少了小鼠心脏中的炎症反应和活性氧（ROS）积累。从机制上讲，我们发现 miR-146a 直接调控 NOX4 的转录，随后影响心肌细胞中的 P38 信号通路。当我们敲低 NOX4 时，miR-146a 拮抗剂在体外实验中使细胞状况恶化的作用被抵消。综上所述，结果表明 miR-146a 通过抑制 NOX4 信号通路来保护心肌免受缺血再灌注损伤。miR-146a 模拟物可能成为心肌缺血再灌注患者的一种潜在治疗方法。
