Cheng Nan, Wang Ming-Yan, Wu Yuan-Bin, Cui Hui-Min, Wei Shi-Xiong, Liu Bing, Wang Rong
Department of Cardiovascular Surgery, PLA General Hospital, Beijing, China.
Front Cell Dev Biol. 2021 Feb 18;8:618574. doi: 10.3389/fcell.2020.618574. eCollection 2020.
Myocardial infarction (MI) is the most prevalent cardiac disease with high mortality, leading to severe heart injury. Circular RNAs (circRNAs) are a new type of regulatory RNAs and participate in multiple pathological cardiac progressions. However, the role of circRNAs Postn (circPostn) in MI modulation remains unclear. Here, we aimed to explore the effect of circPostn on MI-induced myocardial injury and cardiac remodeling. We identified that the expression of circPostn was elevated in the plasma of MI patients, MI mouse model, and hypoxia and reoxygenation (H/R)-treated human cardiomyocytes. The depletion of circPostn significantly attenuated MI-related myocardium injury and reduced the infarct size in MI mouse model. The circPostn knockdown obviously enhanced left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) and inhibited left ventricular anterior wall thickness at diastole (LVAWd) and left ventricular posterior wall thickness at diastole (LVPWd). The depletion of circPostn was able to decrease MI-induced expression of collagen 1α1 and collagen 3α1 in the ventricular tissues of mice. The protein expression of collagen and α-smooth muscle actin (SMA) was up-regulated in MI mice and was inhibited by circPostn knockdown. Meanwhile, the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was repressed by circPostn depletion in the ventricular tissues of MI mice. Besides, the circPostn depletion attenuated cardiomyocyte apoptosis in mice. Mechanically, circPostn served as a miR-96-5p sponge and miR-96-5p-targeted BNIP3 in human cardiomyocytes, in which circPostn up-regulated BNIP3 expression by targeting miR-96-5p. circPostn promoted H/R-induced cardiomyocyte injury by modulating miR-96-5p/BNIP3 axis. Thus, we conclude that circPostn contributes to MI-induced myocardial injury and cardiac remodeling by regulating miR-96-5p/BNIP3 axis. Our finding provides new insight into the mechanism by which circPostn regulates MI-related cardiac dysfunction. circPostn, miR-96-5p, and BNIP3 are potential targets for the treatment of MI-caused heart injury.
心肌梗死（MI）是最常见的心脏疾病，死亡率高，会导致严重的心脏损伤。环状RNA（circRNAs）是一类新型的调控RNA，参与多种心脏病理进程。然而，环状Postn（circPostn）在心肌梗死调控中的作用仍不清楚。在此，我们旨在探讨circPostn对心肌梗死所致心肌损伤和心脏重塑的影响。我们发现，circPostn在心肌梗死患者血浆、心肌梗死小鼠模型以及缺氧复氧（H/R）处理的人心肌细胞中表达升高。circPostn的缺失显著减轻了心肌梗死相关的心肌损伤，并减小了心肌梗死小鼠模型的梗死面积。circPostn敲低明显提高了左心室射血分数（LVEF）和左心室缩短分数（LVFS），并抑制了舒张期左心室前壁厚度（LVAWd）和舒张期左心室后壁厚度（LVPWd）。circPostn的缺失能够降低心肌梗死诱导的小鼠心室组织中Ⅰ型胶原α1（collagen 1α1）和Ⅲ型胶原α1（collagen 3α1）的表达。心肌梗死小鼠中胶原和α平滑肌肌动蛋白（SMA）的蛋白表达上调，而circPostn敲低可抑制这种上调。同时，circPostn缺失抑制了心肌梗死小鼠心室组织中心房钠尿肽（ANP）和脑钠尿肽（BNP）的表达。此外，circPostn缺失减轻了小鼠心肌细胞凋亡。机制上，circPostn在人心肌细胞中作为miR-96-5p的海绵，miR-96-5p靶向BNIP3 [含BH3结构域的凋亡诱导蛋白3（BNIP3）]，其中circPostn通过靶向miR-96-5p上调BNIP3表达。circPostn通过调节miR-96-5p/BNIP3轴促进H/R诱导的心肌细胞损伤。因此，我们得出结论，circPostn通过调节miR-96-5p/BNIP3轴促进心肌梗死所致的心肌损伤和心脏重塑。我们的发现为circPostn调节心肌梗死相关心脏功能障碍的机制提供了新的见解。circPostn、miR-96-5p和BNIP3是治疗心肌梗死所致心脏损伤的潜在靶点。
