LncRNA NAV2-AS2 is critical for fibroblast-to-myofibroblast transition and cardiac fibrosis.

Cardiac fibrosis is a key feature of cardiac remodeling in advanced stages of various cardiovascular diseases. Long non-coding RNAs (lncRNAs) have been shown to play a critical role in the pathogenesis of cardiac fibrosis. The present study uncovered lncRNA NAV2-AS2 as a newfound regulator of cardiac fibrosis, governing fibroblast proliferation and fibroblast-to-myofibroblast transition (FMT). We demonstrate that the expression of NAV2-AS2 is decreased in both fibrotic human heart and murine models of cardiac fibrosis. Knockdown of NAV2-AS2 is sufficient for the induction of fibroblast proliferation and FMT, whereas overexpression of NAV2-AS2 produces the opposite changes. Most importantly, fibroblast-specific transgenic overexpression of NAV2-AS2 in vivo by systemically delivering adeno-associated virus serotype 9 (AAV9) vector rescues cardiac fibrosis and dysfunction induced by both transverse aortic constriction (TAC) and myocardial infarction (MI), whereas knockout of NAV2-AS2 in mice exacerbates the cardiac damage. Mechanistically, NAV2-AS2 is found to act as a competing endogenous RNA (ceRNA) by sponging and inhibiting miR-31. NAV2-AS2 positively regulates Apelin, a critical repressor of proliferation and FMT, by binding to miR-31 and suppressing its degradation of Apelin. Silencing Apelin or overexpression of miR-31 abolishes the anti-fibrotic effects of NAV2-AS2. Additionally, circulating levels of NAV2-AS2 are reduced in the serum of heart failure patients. Collectively, NAV2-AS2 alleviates cardiac fibrosis and improves cardiac function by targeting the miR-31/Apelin axis and can be a potential predictor for heart failure.