miRNA-146a Mimic Inhibits NOX4/P38 Signalling to Ameliorate Mouse Myocardial Ischaemia Reperfusion (I/R) Injury.
miRNA-146a Mimic Inhibits NOX4/P38 Signalling to Ameliorate Mouse Myocardial Ischaemia Reperfusion (I/R) Injury.
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DOI：
10.1155/2021/6366254
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发表时间：
2021
影响因子：
--
通讯作者：
Gao L
中科院分区：
文献类型：
--
作者：
Xiao L;Gu Y;Ren G;Chen L;Liu L;Wang X;Gao L
有证据表明，miR-146 a参与心血管疾病的发病机制;然而，miR-146 a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-146 a在心肌缺血再灌注损伤中的作用及其机制。C57 BL/6 J小鼠缺血45 min再灌注1周，建立心肌I/R损伤模型。在缺血过程开始时静脉内施用miR-146 a模拟物（0.5mg/kg）。新生大鼠心肌细胞也进行缺氧/再灌注（H/R）。用miR-146 a模拟物或拮抗剂处理细胞。结果，miR-146 a模拟物减弱了H/R诱导的心肌细胞损伤，如通过增加的细胞活力和降低的乳酸脱氢酶（LDH）水平所证明的。此外，miR-146 a模拟物抑制了遭受H/R损伤的细胞中的氧化应激。此外，miR-146 a拮抗剂在体外产生不利影响。在心肌I/R损伤的小鼠中，miR-146 a模拟物保留了心脏功能，减少了梗死面积和纤维化。此外，miR-146 a模拟物降低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-146 a直接调节NOX 4的转录，随后影响心肌细胞中的P38信号传导。当我们敲低NOX 4时，miR-146 a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-146 a通过抑制NOX 4信号传导来保护心肌缺血再灌注损伤。miR-146 a模拟物可能成为心肌缺血再灌注患者的潜在治疗方法。
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.
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