Abstract 019: Anti-MicroRNA-144 Therapy Attenuates Progression and Promotes Regression of Atherosclerosis

Rationale: Removal of cholesterol from atherosclerotic lesions remains an unmet therapeutic need. The ATP Binding Cassette Transporter A1 (ABCA1) plays a key role in the efflux of cholesterol from macrophages, therefore strategies that increase macrophage ABCA1 levels are likely to be atheroprotective. Objective: To determine the potential of miR-144 antagonism as an interventional therapeutic in high-fat, high-cholesterol-fed low-density lipoprotein receptor null (Ldlr -/- ) mice. Methods: Ldlr -/- mice were treated with saline, control anti-miR, or anti-miR-144 oligonucleotides once a week for 16 weeks to assess the efficacy of long-term silencing of miR-144 on atherosclerosis progression. Second, Ldlr -/- mice with established atherosclerotic plaques were treated with anti-miR-144 for 4 weeks, in a model of atherosclerosis regression. All anti-miR-144-treated mice showed increased circulating high-density lipoprotein (HDL) levels. Anti-miR-144-treated mice also showed enhanced reverse cholesterol transport to the plasma, liver, and feces in the regression model. Consistent with these observations, all anti-miR-144-treated mice showed reductions in atherosclerotic burden. Notably, miR-144 antagonism also significantly remodeled the HDL particle proteome in both progression and regression models of atherosclerosis. Conclusions: These studies suggest anti-miR-144 treatment may be a promising interventional therapeutic strategy to treat atherosclerotic disease.