MicroRNA-101a inhibits cardiac fibrosis induced by hypoxia via targeting TGFßRI on cardiac fibroblasts.

ABSTRACT

BACKGROUND/AIMS: Hypoxia is a basic pathological challenge that is associated with numerous cardiovascular disorders including aberrant cardiac remodeling. Transforming growth factor beta (TGF-ß) signaling pathway plays a pivotal role in mediating cardiac fibroblast (CF) function and cardiac fibrosis. Recent data suggested that microRNA-101a (miR-101a) exerted anti-fibrotic effects in post-infarct cardiac remodeling and improved cardiac function. This study aimed to investigate the potential relationship between hypoxia, miR-101a and TGF-ß signaling pathway in CFs. METHODS AND RESULTS: Two weeks following coronary artery occlusion in rats, the expression levels of both TGFß1 and TGFßRI were increased, 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 TGFß1 and TGFßRI and the down-regulation of miR-101a. Delivery of miR-101a mimics significantly suppressed the expression of TGFßRI and p-Smad 3, 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 TGFßRI, a target of miR-101a, was validated by luciferase reporter assays targeting the 3'UTR of TGFßRI. Additionally, we found that overexpression of miR-101a reversed the improved migration ability of CFs and further reduced CF proliferation caused by hypoxia. CONCLUSION: Our study illustrates that miR-101a exerts anti-fibrotic effects by targeting TGFßRI, suggesting that miR-101a plays a multi-faceted role in modulating TGF-ß signaling pathway and cardiac fibrosis.