Abstract 199: Specific MicroRNAs Regulate Cardiac Fibroblast-to-Myofibroblast Transition And Fibrosis.
Cardiac fibrosis is the pathological consequence of fibroblast-to-myofibroblast transition (FMT) within the human myocardium, resulting in heart dysfunction. Transforming growth factor-β (TGF-β) plays a pivotal role in the induction of both FMT and cardiac fibrosis. However, the molecular basis of TGF-β-induced FMT in cardiac fibrosis is not clear. In this study, we propose a novel miRNA-mediated approach to attenuate cardiac fibrosis by blocking TGF-β-induced FMT. We observed that the canonical TGF-β/SMAD pathway, and not the MEK pathway, plays a pivotal role in the induction of FMT in primary cultures of human cardiac fibroblasts. Importantly, we have demonstrated that the specific miRNA is significantly upregulated during cardiac FMT. In addition, we observed significant upregulation of the same miRNA in fibrotic human myocardium and two murine models of cardiac fibrosis (transverse aortic constriction and Angiotensin II). Furthermore, overexpression of the miRNA using mimics augmented TGF-β-induced FMT. Downregulation of the miRNA using an antagomiR approach attenuated TGF-β-induced FMT. Notably, in silico analysis and qRT-PCR analysis revealed that this miRNA directly targets apelin, an anti-fibrotic mediator. Next, efficient delivery of cy3-tagged antagomiRs in the heart, liver and spleen was confirmed by confocal microscopy. In vivo silencing of miRNAs in the heart was achieved by systemic delivery of locked nucleic acid (LNA), both in the presence and absence of Angiotensin II. We conclude that TGF-β-induced specific miRNA is both sufficient and necessary for the induction of cardiac FMT and is a novel repressor of apelin. Our data suggests that the inhibition of miRNAs necessary for FMT may serve as a novel therapeutic strategy to prevent human cardiac fibrosis.
Author Disclosures: V. Nagpal: None R. Rai: None A. Place: None S. Murphy: None D.E. Vaughan: None.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
- © 2014 by American Heart Association, Inc.