Abstract 19786: Deficiency of miR-1954 Triggers Cardiac Fibrosis by Targeting Sp1 and Tsp1
Introduction: Cardiac fibrosis which is a severe pathologic manifestation resulting from an injury to the myocardium due to pressure overload, ischemic insult or metabolic stress. In recent years, a small conserved non-coding RNA molecules designated as microRNAs (miRNAs) play dominant role in various aspects of cardiac pathologies including cardiac fibrosis. However, loss of miRNA that contributes to cardiac fibrosis remains elusive.
Hypothesis: Our hypothesis is that deficiency of miR-1954 triggers cardiac fibrosis.
Methods: We exploit next generation sequencing of miRNA for comprehensive and quantitative analyses of dysregulated myocardial miRNAs in cardiac fibrosis as microarray technologies cannot provide adequate sequence coverage. We have identified seven predicted miRNAs sequence following miRPara classification score using wild-type mice infused with Ang II and thoracic aortic constriction (TAC). Among them, one was identified as miR-1954 and was significantly reduced in TAC and Ang II infused mice
Results: The in vitro data demonstrated that depletion of miR-1954 in cardiac fibroblasts (CF) promotes CF proliferation and upregulation of collagen I (Col I). Overexpression of miR-1954 in CF followed by stimulation with Ang II reverses the process implicated an anti-fibrotic mechanism. Interestingly, depletion of miR-1954 in cardiomyocyte (CM) promotes hypertrophy by modulating Sp1 and Gata4; releases soluble factors that trigger CF proliferation. Overexpression of miR-1954 in CM reverses these processes may indicate a cellular cross-talk. Following an unbiased approach, we confirmed that Sp1 and Tsp1 are the bona-fide targets. In vivo study showed that cardiac-specific overexpression of pre-miR-1954 in mice resulted in reduction of cardiac mass, fibrosis, inflammatory responses and improved cardiac function compared to wild- type mice after Ang II treatment. Our findings provide evidence that loss of miR-1954 displays a critical role in the pathogenesis of cardiac fibrosis by directly targeting Sp1-Tsp1-axis and, overexpression of miR-1954 reversed the remodeling process.
Conclusions: We conclude that miR-1954 could be a triggering factor in cardiac fibrosis and providing new information for therapeutic benefit.
Author Disclosures: S. Gupta: Research Grant; Modest; 14GRNT20490320. A.P. Takano: None.
- © 2016 by American Heart Association, Inc.