Abstract 18368: Role of miR-146a in Angiogenesis and Myocardial Regeneration

Abstract

Background Myocardial infarction leads to cardiac remodeling and development of heart failure. Myocardial remodeling and regeneration critically depends on myocardial capillary density after myocardial infarction. However, the underlying mechanisms of myocardial angiogenesis are not well understood. Methods and Results Here, we show that the small noncoding RNA microRNA-146a (miR-146a) is upregulated in ischemic cardiac regions in C57Bl-6 mice following LAD-ligation. In vitro, overexpression of miR-146a significantly attenuates endothelial cell proliferation and migration, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. In contrast, knock-down of miR-146a significantly augments endothelial cell proliferation, migration, network formation and sprouting. So far, IRAK1 and TRAF6, were identified by in silico predictive approaches as direct targets of miR-146a and validated by reciprocal regulation on mRNA and protein levels as well as luciferase gene reporter assays in endothelial cells. In vivo, blocking of endothelial miR-146a significantly enhances angiogenesis as determined by matrigel plug assays. Moreover, inhibition of miR-146a by systemic application of specific antagomirs enhances myocardial vascularity and limits myocardial infarct size in mice, which results in preserved cardiac function (FS: 22±4 vs. 11±2; n=6; P<0.01). Conclusions Our findings indicate that miR-146a acts as a critical regulator of endothelial cell angiogenesis during myocardial regeneration. Moreover, miR-146a may represent an attractive target for future therapeutic interventions for the treatment of ischemic heart disease.