Overexpression of circRNA SNRK targets miR-103-3p to reduce apoptosis and promote cardiac repair through GSK3β/β-catenin pathway in rats with myocardial infarction.
Overexpression of circRNA SNRK targets miR-103-3p to reduce apoptosis and promote cardiac repair through GSK3β/β-catenin pathway in rats with myocardial infarction.
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circRNA SNRK 过表达靶向 miR-103-3p，通过 GSK3β/β-catenin 通路减少心肌梗死大鼠的细胞凋亡并促进心脏修复
DOI：
10.1038/s41420-021-00467-3
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发表时间：
2021-04-19
影响因子：
7
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Zhu Y;Zhao P;Sun L;Lu Y;Zhu W;Zhang J;Xiang C;Mao Y;Chen Q;Zhang F
缺血性心肌病严重危害人类健康，预后不良。急性心肌梗死(AMI)是急性心肌梗死的主要病因，其病理生理过程是由于冠状动脉内急性和持续性的缺血缺氧导致心肌细胞死亡。我们发现了一个在心肌梗死(MI)大鼠中表达下调的CircRNA(CircSNRK)，然而，它在MI环境中所起的作用尚不清楚。本研究通过实验研究了CircSNRK在心脏存活调节中的作用，并探讨了CircSNRK功能的机制。采用实时定量聚合酶链式反应(qRT-PCR)检测心肌中CircSNRK的表达模式。此外，还进行了体外和体内的功能获得试验，以确定CircSNRK在心脏修复中的作用。采用定量逆转录聚合酶链式反应(QRT-PCR)、免疫印迹和荧光素酶报告分析等方法研究了CircRNA与miRNAs的相互作用。心肌细胞过表达CircSNRK可减少细胞凋亡，促进细胞增殖。腺相关病毒9(AAV9)介导的CircSNRK在心肌梗死后心肌过表达，减少心肌细胞凋亡，促进心肌细胞增殖，促进血管生成，改善心功能。总体而言，CircSNRK的上调促进了心肌梗死后的心脏存活和功能恢复。在机制上，CircSNRK作为miR-103-3p的海绵，通过诱导SNRK表达增加，与GSK3β结合，调节其磷酸化活性，从而调控心肌细胞的凋亡和增殖。因此，CircSNRK可能是改善MI后临床预后的一个有前途的治疗靶点。
Ischemic cardiomyopathy seriously endangers human health leading to a poor prognosis. Acute myocardial infarction (AMI) is the primary etiology, and the pathophysiological process concludes with the death of cardiomyocytes caused by acute and persistent ischemia and hypoxia in the coronary arteries. We identified a circRNA (circSNRK) which was downregulated in rats with myocardial infarction (MI), however, the role it plays in the MI environment is still unclear. This study contained experiments to investigate the role of circSNRK in the regulation of cardiac survival and explore the mechanisms underlying circSNRK functions. Quantitative real-time PCR (qRT-PCR) was performed to determine the circSNRK expression patterns in hearts. Gain-of-function assays were also conducted in vitro and in vivo to determine the role of circSNRK in cardiac repair. qRT-PCR, western blot, and luciferase reporter assays were used to study circRNA interactions with micro RNAs (miRNAs). Overexpression of circSNRK in cardiomyocytes reduced apoptosis and increased proliferation. Adeno associated virus 9 (AAV9) mediated myocardium overexpression of circSNRK in post MI hearts reduced cardiomyocyte apoptosis, promoted cardiomyocyte proliferation, enhanced angiogenesis, and improved cardiac functions. Overall, upregulation of circSNRK promotes cardiac survival and functional recovery after MI. Mechanistically, circSNRK regulates cardiomyocyte apoptosis and proliferation by acting as a miR-103-3p sponge and inducing increased expression of SNRK which can bind GSK3β to regulate its phosphorylated activity. And thus circSNRK may be a promising therapeutic target for improving clinical prognosis after MI.
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