Abstract 634: Silencing miR144 Enhances Regression and Attenutates Progression of Atherosclerosis

Cholesterol imbalance plays a central role in multiple diseases, particularly cardiovascular disease, the leading cause of death in the United States. Lipid-loaded macrophage foam cells are a critical determining factor in the pathogenesis of atherosclerosis. MicroRNAs are small non-coding RNA molecules that regulate both cholesterol and lipoprotein metabolism, and may significantly contribute to disease progression. We previously identified miR-144 as a novel regulator of lipid metabolism that is also regulated by the nuclear receptor farnesoid X receptor (FXR). We identified the cholesterol transporter ABCA1 as a miR-144 target gene, and showed that increased hepatic expression of miR-144 decreased ABCA1 protein and plasma cholesterol levels. Consequently, we hypothesized that silencing miR-144 may have therapeutic potential because it may increase the levels of atheroprotective HDL particles and enhance reverse cholesterol transport (RCT) due to increased ABCA1 levels in macrophages. Here we present en face analysis of atherosclerosis showing that silencing miR-144 both enhanced regression and attenuated progression of atherosclerosis. In addition, we demonstrate that silencing miR-144 enhances RCT, the process by which macrophage cholesterol is returned to the liver for excretion. Together, these data suggest that this pathway may represent a bona-fide strategy to treat atherosclerosis.