Zhu Yeqian, Zhao Pengcheng, Sun Ling, Lu Yao, Zhu Wenwu, Zhang Jian, Xiang Chengyu, Mao Yangming, Chen Qiushi, Zhang Fengxiang
Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Department of Cardiology, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China.
Cell Death Discov. 2021 Apr 19;7(1):84. doi: 10.1038/s41420-021-00467-3.
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.
缺血性心肌病严重危害人类健康，预后较差。急性心肌梗死（AMI）是主要病因，其病理生理过程以冠状动脉急性持续性缺血缺氧导致心肌细胞死亡告终。我们鉴定出一种在心肌梗死（MI）大鼠中表达下调的环状RNA（circSNRK），然而，其在MI环境中所起的作用仍不清楚。本研究通过实验探讨circSNRK在调节心脏存活中的作用，并探索circSNRK功能的潜在机制。采用定量实时PCR（qRT-PCR）检测心脏中circSNRK的表达模式。还在体外和体内进行了功能获得实验，以确定circSNRK在心脏修复中的作用。采用qRT-PCR、蛋白质免疫印迹法和荧光素酶报告基因检测法研究circRNA与微小RNA（miRNA）的相互作用。在心肌细胞中过表达circSNRK可减少细胞凋亡并增加细胞增殖。腺相关病毒9（AAV9）介导的circSNRK在MI后心脏中的心肌过表达可减少心肌细胞凋亡，促进心肌细胞增殖，增强血管生成，并改善心脏功能。总体而言，circSNRK的上调促进MI后心脏存活和功能恢复。机制上，circSNRK通过充当miR-103-3p的海绵，诱导可与GSK3β结合以调节其磷酸化活性的SNRK表达增加，从而调节心肌细胞凋亡和增殖。因此，circSNRK可能是改善MI后临床预后的一个有前景的治疗靶点。
