Liu Xinxin, Dou Bo, Tang Wenqiang, Yang Huan, Chen Kemin, Wang Yuxia, Qin Jie, Yang Fengrui
Department of Anesthesiology, The First People's Hospital of Huaihua, Huaihua 418000, PR China.
Department of Anesthesiology, The First Affiliated Hospital of University of South China, Hengyang 421001, PR China.
Int Immunopharmacol. 2023 Apr;117:110006. doi: 10.1016/j.intimp.2023.110006. Epub 2023 Mar 13.
Novel mechanistic insights into the effects of circular RNAs (circRNAs) on the physiology and pathology of cardiovascular diseases are under increasingly active investigation. This study defined the cardioprotective role and mechanistic actions of circ_0002612 in myocardial ischemia/reperfusion injury (MI/RI).
MI/RI was induced in mice by ligation of the left anterior descending (LAD) artery followed by reperfusion, and the in vitro model was established in cultured cardiomyocytes under hypoxia/reoxygenation (H/R) conditions. Interaction among circ_0002612, miR-30a-5p, Ppargc1a, and NLRP3 was predicted by bioinformatics analysis and further experimentally identified. Gain- and loss-of-function experiments were performed to evaluate the effect of the circ_0002612/miR-30a-5p/Ppargc1a/NLRP3 axis on the cardiac function and myocardial infarction of I/R-injured mice, as well as viability and apoptosis of H/R-challenged cardiomyocytes.
In the myocardial tissues of MI/RI mice, miR-30a-5p was negatively correlated with circ_0002612 or Ppargc1a, but circ_0002612 was positively correlated with the expression of Ppargc1a. circ_0002612 competitively bound to miR-30a-5p to release expression of its target gene Ppargc1a. circ_0002612 promoted cardiomyocyte viability while suppressing the apoptosis by impairing the miR-30a-5p-mediated inhibition of Ppargc1a. Additionally, Ppargc1a inhibited the expression of NLRP3 and consequently facilitated cardiomyocyte proliferation while suppressing cell apoptosis. By inhibiting the expression of NLRP3, circ_0002612 protected mice from MI/RI.
Overall, this study demonstrates the cardioprotective role of circ_0002612 against MI/RI, which may be a viable target for MI/RI.
关于环状RNA（circRNA）对心血管疾病生理和病理影响的新机制见解正在受到越来越积极的研究。本研究确定了circ_0002612在心肌缺血/再灌注损伤（MI/RI）中的心脏保护作用及其作用机制。
通过结扎左冠状动脉前降支（LAD）诱导小鼠MI/RI，随后进行再灌注，并在缺氧/复氧（H/R）条件下的培养心肌细胞中建立体外模型。通过生物信息学分析预测circ_0002612、miR-30a-5p、Ppargc1a和NLRP3之间的相互作用，并进一步通过实验进行鉴定。进行功能获得和功能丧失实验，以评估circ_0002612/miR-30a-5p/Ppargc1a/NLRP3轴对I/R损伤小鼠心脏功能和心肌梗死的影响，以及对H/R刺激的心肌细胞活力和凋亡的影响。
在MI/RI小鼠的心肌组织中，miR-30a-5p与circ_0002612或Ppargc1a呈负相关，但circ_0002612与Ppargc1a的表达呈正相关。circ_0002612竞争性结合miR-30a-5p以释放其靶基因Ppargc1a的表达。circ_0002612通过削弱miR-30a-5p介导的对Ppargc1a的抑制作用，促进心肌细胞活力，同时抑制细胞凋亡。此外，Ppargc1a抑制NLRP3的表达，从而促进心肌细胞增殖，同时抑制细胞凋亡。通过抑制NLRP3的表达，circ_0002612保护小鼠免受MI/RI。
总体而言，本研究证明了circ_0002612对MI/RI具有心脏保护作用，这可能是MI/RI的一个可行靶点。
