MicroRNA-101a Inhibits Cardiac Fibrosis Induced By Hypoxia Via Targeting TGFβRI On Cardiac Fibroblasts

Background:Hypoxia is a basic pathological change that is associated with a variety of cardiovascular diseases and may lead to aberrant cardiac remodeling. Transforming growth factor beta (TGF-β) signaling pathway plays important roles in in the regulation of cardiac fibroblasts (CFs) function and cardiac fibrosis. Recent data suggested that microRNA-101a (miR-101a) exerted anti-fibrotic effects in post-infarct cardiac fibrosis and improved cardiac function.Aims:This study aimed to investigate the potential relationship among hypoxia, miR-101a and TGF-β signaling pathway in myocardial tissue in vivo and CFs in vitro.Methods and Results:Two weeks after coronary artery ligation in rats, the expression levels of both TGFβ1and TGFβRI were elevated, but the expression of miR-101a was decreased at the site of the infarct and along its border. Cultured rat neonatal CFs treated with hypoxia were characterized by the up-regulation of TGFβ1and TGFβRI and the down-regulation of miR-101a. Delivery of miR-101a mimic significantly suppressed the expression of TGFβRI and p-Smad3(but not with the TGF β1), CF differentiation and collagen content of CFs. These anti-fibrotic effects were abrogated by co-transfection with AMO-miR-101a, an antisense inhibitor of miR-101a. The repression of TGFβRI, a target of miR-101a, was validated by luciferase reporter assays targeting the3’UTR of TGFβRI. Additionally, we found that over-expression of miR-101a reversed the improved migration ability of CFs and further reduced CF proliferation caused by hypoxia.Conclusion:Our findings indicate that miR-101a exerts anti-fibrotic effects by targeting TGFβRI, suggesting that miR-101a plays a multi-faceted role in modulating TGF-β signaling pathway and cardiac fibrosis.