State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Shanghai Arrhythmias Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Laboratory of Molecular Genetics and Stem Cell Differentiation, Tongji University School of Medicine, Shanghai 200120, China.
Department of Cardiology, Shanghai Shibei Hospital, Shanghai 200435, China.
J Genet Genomics. 2024 Aug;51(8):844-854. doi: 10.1016/j.jgg.2024.03.010. Epub 2024 Apr 2.
Pathological myocardial hypertrophy is a common early clinical manifestation of heart failure, with noncoding RNAs exerting regulatory influence. However, the molecular function of circular RNAs (circRNAs) in the progression from cardiac hypertrophy to heart failure remains unclear. To uncover functional circRNAs and identify the core circRNA signaling pathway in heart failure, we construct a global triple network (microRNA, circRNA, and mRNA) based on the competitive endogenous RNA (ceRNA) theory. We observe that cardiac hypertrophy-related circRNA (circRNA CHRC), within the ceRNA network, is down-regulated in both transverse aortic constriction mice and Ang-II--treated primary mouse cardiomyocytes. Silencing circRNA CHRC increases cross-sectional cell area, atrial natriuretic peptide, and β-myosin heavy chain levels in primary mouse cardiomyocytes. Further screening shows that circRNA CHRC targets the miR-431-5p/KLF15 axis implicated in heart failure progression in vivo and in vitro. Immunoprecipitation with anti-Ago2-RNA confirms the interaction between circRNA CHRC and miR-431-5p, while miR-431-5p mimics reverse Klf15 activation caused by circRNA CHRC overexpression. In summary, circRNA CHRC attenuates cardiac hypertrophy via sponging miR-431-5p to maintain the normal level of Klf15 expression.
病理性心肌肥厚是心力衰竭的常见早期临床表现，非编码 RNA 发挥着调节作用。然而，环状 RNA（circRNA）在心肌肥厚向心力衰竭进展过程中的分子功能尚不清楚。为了揭示功能性 circRNA 并鉴定心力衰竭核心 circRNA 信号通路，我们基于竞争内源性 RNA（ceRNA）理论构建了一个全局三重网络（miRNA、circRNA 和 mRNA）。我们观察到，ceRNA 网络中的心脏肥厚相关 circRNA（circRNA CHRC）在横主动脉缩窄小鼠和 Ang-II 处理的原代小鼠心肌细胞中均下调。沉默 circRNA CHRC 会增加原代小鼠心肌细胞的横截面积、心房利钠肽和β-肌球蛋白重链水平。进一步筛选表明，circRNA CHRC 靶向 miR-431-5p/KLF15 轴，该轴与体内和体外心力衰竭进展有关。用抗 Ago2-RNA 进行免疫沉淀证实了 circRNA CHRC 与 miR-431-5p 之间的相互作用，而 miR-431-5p 模拟物逆转了 circRNA CHRC 过表达引起的 Klf15 激活。综上所述，circRNA CHRC 通过海绵吸附 miR-431-5p 来减轻心肌肥厚，从而维持 Klf15 表达的正常水平。
