The cardiac protective human circular RNA circKLHL20_009 sponges miR-31-5p to ameliorate myocardial hypertrophy and fibrosis through suppressing β-catenin signaling.

Circular RNAs (circRNAs) participate in the process of pathological cardiac remodeling; however, the roles of dysregulated circRNAs remain unclear. In this study, we revealed that the expression of the circRNA circKLHL20_009 was significantly upregulated in the myocardium of patients with heart failure (HF) and in human cardiomyocytes treated with angiotensin II (Ang II). In vivo, the cardiac-specific expression of circKLHL20_009 ameliorated transverse aortic constriction (TAC) surgery-induced cardiac remodeling in mice. The enforced expression of circKLHL20_009 abolished Ang II-induced cardiomyocyte hypertrophy and the fibrotic phenotypes of cardiac fibroblasts, and it mitigated cryoinjury-induced cardiac organ fibrosis. Mechanistically, circKLHL20_009 specifically sponged miR-31-5p to increase Dickkopf-1 (DKK1) expression and inactivate β-catenin signaling in an LRP6-dependent manner, thereby decreasing the expression of genes related to cardiac hypertrophy and fibrosis. Notably, we designed and demonstrated that an artificial circRNA sponge, circSPmiR31, which contains six repeats of the miR-31-5p binding site, effectively mitigated cardiac hypertrophy and fibrosis by suppressing miR-31-5p binding to Dkk1 mRNA. These results provide new insights into the development of therapeutics for cardiac remodeling based on a circularized RNA sponge targeting miR-31-5p. The human circKLHL20_009 ameliorates cardiac remodeling through the DKK1-LRP6/β-catenin axis via sponging miR-31-5p. The artificial circRNA sponge, circSPmiR31, effectively mitigates cardiac hypertrophy and fibrosis through inhibiting miR-31-5p binding to Dkk1 mRNA, holding a therapeutic promise in cardiac hypertrophy and fibrosis, and HF.