Pathological myocardial hypertrophy is a common early clinical manifestation of heart failure, with noncoding RNAs exerting regulatory influence. However, the molecular function of circular ribonucleic acids (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 circRNA CHRC, within the ceRNA network, is down-regulated in both transverse aortic constriction (TAC) 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 reveals 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 activation caused by circRNA CHRC overexpression. In summary, circRNA CHRC attenuates cardiac hypertrophy via sponging miR-431-5p to maintain the normal level of expression.

中文翻译：

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环状核糖核酸CHRC通过miR-431-5p/KLF15信号轴在心力衰竭进展中的功能作用

病理性心肌肥厚是心力衰竭常见的早期临床表现，非编码RNA发挥调节作用。然而，环状核糖核酸（circRNA）在心脏肥大到心力衰竭进展中的分子功能仍不清楚。为了揭示功能性circRNA并确定心力衰竭中的核心circRNA信号通路，我们基于竞争性内源RNA（ceRNA）理论构建了全局三重网络（microRNA、circRNA和mRNA）。我们观察到，ceRNA 网络内的 circRNA CHRC 在主动脉横缩（TAC）小鼠和 Ang-II 处理的原代小鼠心肌细胞中下调。沉默 circRNA CHRC 可增加原代小鼠心肌细胞的横截细胞面积、心房钠尿肽和 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，与体内和体外心力衰竭进展有关。使用抗 Ago2-RNA 进行免疫沉淀证实了 circRNA CHRC 和 miR-431-5p 之间的相互作用，而 miR-431-5p 模拟了 circRNA CHRC 过表达引起的反向激活。总之，circRNA CHRC 通过海绵 miR-431-5p 来维持正常的表达水平，从而减轻心脏肥大。