Abstract 12623: MiR-125b is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis
Objective: Fibroblast-to-myofibroblast transition (FMT) within the heart is the predominant cause of cardiac fibrosis, resulting in cardiac dysfunction. Transforming growth factor-β (TGF-β) plays a pivotal role in the induction of both FMT and cardiac fibrosis. However, the role of miRNAs in TGF-β-induced FMT and cardiac fibrosis remains largely unexplored. In this study, we propose a novel miRNA-mediated approach to attenuate cardiac fibrosis by blocking TGF-β-induced FMT.
Methods and Results: We observed that the canonical TGF-β/SMAD pathway and not the MEK pathway played a pivotal role in the induction of FMT in primary cultures of human cardiac fibroblasts (HCFs). Importantly, we demonstrate for the first time that miR-125b is significantly upregulated during cardiac FMT. We observed significant upregulation of miR-125b in fibrotic human myocardium and two murine models of cardiac fibrosis (transverse aortic constriction and Angiotensin II infusion). Overexpression of miR-125b using specific miRNA mimics augmented TGF-β-induced FMT, while downregulation of miR-125b using an antagomiR approach attenuated TGF-β-induced FMT. Notably, in silico analysis and qRT-PCR analysis revealed that miR-125b directly targets apelin, an anti-fibrotic mediator. In addition, we observed that treatment with Apelin in HCFs prevents TGF-β-induced FMT, whereas suppression of endogenous apelin potentiated TGF-β-induced FMT. Next, in vivo silencing of miR-125b was achieved by systemic delivery of locked nucleic acid (LNA) against miR-125b both in the presence and absence of Angiotensin II. Most importantly, inhibition of miR-125b protected against both perivascular and interstitial cardiac fibrosis in vivo.
Conclusions: In conclusion, our findings indicate that TGF-β-induced miR-125b is necessary for the induction cardiac fibrosis. In addition, miR-125b is necessary and sufficient to induce FMT by repressing apelin. Our data suggests that the inhibition of miR-125b may serve as a novel therapeutic target to prevent human cardiac fibrosis.
Author Disclosures: V. Nagpal: Research Grant; Modest; AHA Pre-doctoral Fellowship (VN) 14PRE18840028 . Other Research Support; Significant; NIH/NHLBI 1P01HL108795-01. R. Rai: None. A.T. Place: None. S.B. Murphy: None. A.K. Ghosh: None. D.E. Vaughan: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.