Pro-fibrotic and apoptotic activities of circARAP1 in myocardial ischemia–reperfusion injury

Abstract

Reperfusion modality can cause damage to cardiomyocytes, known as myocardial ischemia–reperfusion injury (MI/RI). Circular RNAs (circRNAs) are fundamental regulators associated with many cardiac diseases, including MI/RI. However, their functional impact on cardiomyocyte fibrosis and apoptosis remains elusive. Therefore, this study aimed to explore possible molecular mechanisms of circARPA1 in animal models and in hypoxia/reoxygenation (H/R)-treated cardiomyocytes. GEO dataset analysis showed that has_circ_0023461 (circARPA1) was differentially expressed in myocardial infarction samples. Real-time quantitative PCR further supported that circARPA1 was expressed at high levels in animal models and in H/R-triggered cardiomyocytes. Then, loss-of-function assays were performed to show that circARAP1 suppression effectively ameliorated cardiomyocyte fibrosis and apoptosis in MI/RI mice. Mechanistic experiments showed that miR-379-5p, KLF9 and Wnt signaling pathways were associated with circARPA1. circARPA1 can sponge miR-379-5p to regulate KLF9 expression, thereby activating the wnt/β-catenin pathway. Finally, gain-of-function assays revealed that circARAP1 aggravated MI/RI in mice and H/R-induced cardiomyocyte injury by regulating the miR-379-5p/KLF9 axis to activate Wnt/β-catenin signaling.