Abstract 52: PPAR-γ Targeted by MicroRNA-130a Regulates Angiotensin II-Induced Cardiac Fibrosis
Aims: Cardiac fibrosis which occurs due to disruption of extracellular matrix network resulted in the accumulation of excess collagens and other matrix components leading to myocardial dysfunction.
Angiotensin II (Ang II), a critical effector of this system has been implicated in the development of hypertension-induced cardiac fibrosis. In recent years, miRNAs have identified as an attractive targets for therapeutic intervention in various disease pathologies including cardiac fibrosis. However, the exact effect and underlying mechanism of miRNAs in cardiac fibrosis remains unclear. Here, we sought to investigate and test our hypothesis that miR-130a plays a critical role in the development of myocardial fibrosis by restoring PPARγ level.
Methods and Results: We have identified a panel of novel miRNAs via miRNA array in Ang II infused mice heart. Among them, we found that miR-130a was upregulated both in pressure overload and Ang II infused models targeting PPARγ. Overexpressing miR-130a in cardiac fibroblast promoted the pro-fibrotic gene expression (collagen I/III, fibronectin and CTGF) and myofibroblasts differentiation. Inhibition miR-130a reversed the process and weakened these activities. Using luciferase-linked constitutive and dominant negative constructs of PPARγ, we determined the underlying mechanism of cardiac fibrosis occurred via targeting PPARγ. The in vivo inhibition of miR-130a by subcutaneous injections of LNA-based anti-miR-130a in mice subjected to Ang II infusion significantly reduced the severity of cardiac fibrosis, hypertrophy. The protective mechanism is associated with restoration of PPARγ level, reduction of pro-fibrotic genes and apoptosis; reversion of myofibroblasts differentiation and improved cardiac function.
Conclusions: Our findings provide evidence that miR-130a plays a critical role in the progression of cardiac fibrosis by directly targeting PPARγ, and that inhibition of miR-130a reversed the cardiac fibrosis. We conclude that miR-130a may be a new marker for cardiac fibrosis and inhibition of miR-130a would be a promising strategy in the treatment of cardiac fibrosis.
Author Disclosures: S. Gupta: None. L. Li: None.
This research has received full or partial funding support from the American Heart Association, South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).
- © 2015 by American Heart Association, Inc.