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 diabetes. However, the underlying mechanisms of cardiac fibrosis remain unclear. This study aimed to investigate the role of the long non-coding RNA (LncRNA) Airn in the pathogenesis of cardiac fibrosis in diabetic cardiomyopathy (DCM) and its underlying mechanism. METHODS: Diabetes mellitus (DM) was induced in mice by streptozotocin injection. An intramyocardial adeno-associated virus (AAV) was used to manipulate Airn expression. The functional significance and underlying mechanisms in DCM fibrosis were investigated both in vitro and in vivo. RESULTS: Diabetic hearts showed a significant impairment in cardiac function, accompanied by obviously increased cardiac fibrosis. Interestingly, lncRNA Airn expression was significantly decreased in both diabetic hearts and high glucose (HG)-treated cardiac fibroblasts (CFs). AAV-mediated Airn reconstitution prevented cardiac fibrosis and the development of DCM, while Airn knockdown induced cardiac fibrosis phenotyping DCM. As in vitro, Airn reversed HG-induced fibroblast-myofibroblast transition, aberrant CFs proliferation and section of collagen I. In contrast, Airn knockdown mimicked a HG-induced CFs phenotype. Mechanistically, we identified that Airn exerts anti-fibrotic effects by directly binding to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) and further prevents its ubiquitination-dependent degradation. Moreover, we revealed that Airn/IMP2 protected p53 mRNA from degradation in m6A manner, leading to CF cell cycle arrest and reduced cardiac fibrosis. As a result, ablation of p53 blunted the inhibitory effects of Airn on fibroblast activation and cardiac fibrosis. CONCLUSIONS: Our study demonstrated for the first time that Airn prevented the development of cardiac fibrosis in diabetic heart via IMP2-p53 axis in an m6A dependent manner. LncRNA Airn could be a promising therapeutic target for cardiac fibrosis in DCM. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13062-022-00346-6.