LncRNA Airn alleviates diabetic cardiac fibrosis by inhibiting activation of cardiac fibroblasts via a m6A-IMP2-p53 axis

Background Cardiac fibrosis is a leading cause of cardiac dysfunction in patients with diabetic cardiomyopathy (DCM), leading to early impaired myocardial compliance and late heart failure. However, the underlying mechanism remains largely unclear. This study aims to investigate the role of LncRNA Airn in the pathogenesis of cardiac fibrosis in DCM and its underlying mechanism. Methods Diabetic mellitus were induced by streptozotocin (STZ) injection. Intramyocardial adeno-associated virus (AAV) was employed to manipulate Airn expression. Multiple approaches including echocardiography, m6A-RNA immunoprecipitation, RNA pull-down and RNA-FISH staining were performed in-vivo and in-vitro. Results Airn was significantly lower in the hearts of diabetic mice, accompanied by evident cardiac dysfunction. AAV-mediated Airn overexpression restored cardiac function and prevented cardiac fibrosis in diabetic mice. During the in-vitro experiments, Airn exerted its anti-fibrogenesis effects in HG-treated cardiac fibroblasts (CFs) by reducing the expression of cardiac fibrotic markers and inhibiting CFs proliferation. Mechanistically, RNA pull-down and RIP assays indicated that Airn bond to insulin-like growth factor 2 mRNA-binding protein2 (IMP2) and prevented its ubiquitination-dependent degradation. Further analyze revealed Airn/IMP2 identified the m6A modification in p53 mRNA and protected p53 mRNA from degradation, leading to CFs cell cycle arrest and reduced cardiac fibrosis. In contrast, Ablation of p53 blunted the inhibitory effects of Airn on fibroblasts activation. Conclusions Our study demonstrated for the first time that LncRNA Airn prevented the development of cardiac fibrosis in diabetic heart via a m6A-IMP2-p53 axis. LncRNA Airn could be a promising therapeutic target for cardiac fibrosis in DCM.