Abstract 19546: Silencing miR-144 Enhances Regression and Reduces Progression of Atheroscleoris

Enhancing cholesterol removal from macrophages in atherosclerotic plaques remains a major unmet pharmacological need. MicroRNA therapeutics are one approach that is currently being evaluated. MicroRNAs fine tune gene expression, and those that target ABCA1, the major cholesterol efflux transporter, are candidates for therapeutic approaches. Silencing microRNAs that target ABCA1 result in increased ABCA1 levels and activity and therefore enhance lipid removal from lesion macrophages. We previously showed that miR-144 targets ABCA1 by binding to at least 2 binding sites in the 3’ UTR region. We have now tested whether silencing miR-144, which increases ABCA1, affects atherosclerosis in two models. First, LDLR-/- mice were fed a western-type diet for 16 weeks, before being switched to regular rodent chow to promote lesion regression. One group of mice were sacrificed after 16 weeks of western diet (baseline), and the remaining animals were randomly assigned to one of 3 groups; vehicle (PBS), control anti-miR, or anti-miR-144 for 4 weeks. Silencing miR-144 significantly decreased atherosclerosis by en face analysis by 20% compared to either control. Further, silencing miR-144 modestly increased plasma HDL levels by 14%, in line with previous studies. To determine whether silencing miR-144 enhanced macrophage cholesterol efflux in mice, we used the same experimental approach. However, 2 days prior to the sacrifice, mice were injected with macrophages that had been loaded with radiolabelled cholesterol. Silencing miR-144 in vivo enhanced macrophage cholesterol efflux to plasma, liver and feces, suggesting the mechanism for the reduced atherosclerosis is due to increased cholesterol removal from plaques. Finally, we also determined whether silencing miR-144 decreased progression of atherosclerosis. LDLR-/- mice were fed a western-style diet for 16 weeks, and, at the same time, mice were treated mice with either anti miR-144, control anti miR or vehicle (PBS). Silencing miR-144 decreased atherosclerosis progression by 33% relative to controls, while HDL levels were also modestly increased (19%). Our results indicate that silencing miR-144 is a potential therapeutic strategy to reduce atherosclerosis, in both regression and progression models.