Identifying an Atherogenic Role for Vascular Smooth Muscle Cell miR-33a Expression

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PROJECT SUMMARY/ABSTRACT Atherosclerosis is a disease that is the result of cholesterol accumulating within arteries. Atherosclerosis is the leading cause of death both within the United States and worldwide due to this disease being the primary cause of myocardial infarctions and ischemic strokes. Therefore, improving therapies for atherosclerosis may drastically decrease the number of deaths from ischemic strokes and myocardial infarctions. Preventing cholesterol accumulation within arteries via increasing the removal of cholesterol in the smooth muscle cells of arteries is one potential strategy to treat atherosclerosis. Excessive cholesterol accumulation in arterial smooth muscle cells may be caused by miR-33a expression in these cells, since miR-33a promotes cellular cholesterol retention, and therefore inhibiting miR-33a in arterial smooth muscle cells may be atheroprotective. The goal of this project is to test whether miR-33a expression in arterial smooth muscle cells is pro-atherogenic. There is 1 in vitro Aim and 1 in vivo Aim. The in vitro Aim tests whether inhibiting miR-33a in cultured vascular smooth muscle cells increases the removal of cholesterol via enhancing cholesterol efflux. The in vivo Aim tests whether deleting miR-33a in vascular smooth muscle cells decreases lipid content and reduces lesion area within the aortas of fat-fed pro-atherogenic mouse models. Success with both Specific Aims will imply that miR-33a expression within arterial smooth muscle cells is pro- atherogenic and this is at least partially due to decreasing intracellular cholesterol efflux. Therefore, achievement of these Aims will show proof-of-concept that inhibiting miR-33a specifically in arterial smooth muscle cells may be an innovative approach to treating atherosclerosis.