miR-101 Inhibited Post-Infarct Cardiac Fibrosis and Improved Left Ventricular Compliance via FOS/TGFβ1 Pathway
Background—Cardiac interstitial fibrosis is a major cause of the deteriorated performance of the heart in patients with chronic myocardial infarction. MicroRNAs have recently been proven a novel class of regulators of cardiovascular diseases, including those associated with cardiac fibrosis. This study aimed to explore the role of miR-101 in cardiac fibrosis and the underlying mechanisms.
Methods and Results—Four weeks after coronary artery ligation of rats, the expression of miR-101a and miR-101b (miR-101a/b) in the peri-infarct area was decreased. Treatment of cultured rat neonatal cardiac fibroblasts (CFs) with angiotensin II (AngII) also suppressed the expression of miR-101a/b. Forced expression of miR-101a/b suppressed the proliferation and collagen production in rat neonatal CFs, as revealed by cell counting, MTT assay and qRT-PCR. The effect was abrogated by co-transfection with AMO-101a/b, the antisense inhibitors of miR-101a/b. c-Fos was found to be a target of miR-101a as overexpression of miR-101a decreased the protein and mRNA levels of c-Fos and its downstream protein TGFβ1. Silencing c-Fos by small interfering RNA mimicked the anti-fibrotic action of miR-101a, whereas forced expression of c-Fos protein canceled the effect of miR-101a in cultured CFs. Strikingly, echocardiography and hemodynamic measurements indicated remarkable improvement of the cardiac performance 4-weeks after adenovirus mediated overexpression of miR-101a in rats with chronic myocardial infarction. Furthermore, the interstitial fibrosis was alleviated and the expression of c-Fos and TGFβ1 was inhibited.
Conclusions—Overexpression of miR-101a can mitigate interstitial fibrosis and the deterioration of cardiac performance in post-infarct rats, indicating the therapeutic potential of miR-101a for cardiac disease associated with fibrosis.
- Received January 20, 2012.
- Accepted June 15, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited