Novel Mechanisms Underlying the Development of Atherosclerosis

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Project Summary Coronary atherosclerosis is one of five top causes for cardiovascular (CV) hospitalization in U.S. Veterans. Atherosclerosis is a complex and progressive disease characterized by the buildup of plaques composed of lipid- rich foam cells, inflammatory cells, and fibrous elements in the arterial intima. Atherosclerosis is associated with high risks of acute myocardial infarction, heart failure, and stroke, which are the additional three of top five causes for Veterans cardiovascular hospitalization. It is well established that vascular smooth muscle cell (SMC) and nuclear factor (NF)-kB signaling contribute to development and progression of atherosclerosis. However, the factors and mechanisms that govern SMC function in atherosclerosis, remain largely unknown. Our exciting preliminary data indicate that Olfactomedin 2 (Olfm2) plays an essential role in the development of atherosclerosis. Olfm2 is induced in lipid-loading SMCs during SMC foam cell formation and in mouse and human atherosclerotic lesions. Importantly, Olfm2 deficiency (Olfm2-/-) inhibits high fat diet-induced atherosclerotic plaque formation and improves plaque stability in advanced atherosclerosis. Biochemically, Olfm2-/- elevates serum level of high-density lipoprotein-cholesterol while downregulates the expression of acyl- coenzyme A: cholesterol acyltransferase-1 (ACAT1) in aortas of ApoE-/- mice. ACAT1 converts free cholesterol into cholesteryl esters for storage in lipid droplets and thus promotes foam cell formation in atherosclerotic lesion. In vitro studies showed that knockdown of Olfm2 inhibits while overexpression of Olfm2 promotes lipid accumulation and CCAAT/enhancer-binding protein homologous protein (CHOP) expression in oxidized low- density lipoprotein-treated SMCs. These data strongly support a novel hypothesis that Olfm2 promotes atherosclerosis by mediating SMC foam cell formation and apoptosis. Using primary human coronary artery SMCs, Olfm2-/- mouse SMCs, and SMC lineage-tracing Olfm2-/- mice combining with molecular, cellular, histological, and pharmacological approaches, we will 1) test if Olfm2 promotes SMC foam cell formation and mediates SMC foam cell apoptosis; 2) determine the molecular mechanisms underlying Olfm2 function in mediating SMC foam cell formation and apoptosis; and 3) determine the cell-specific roles of Olfm2 in atherosclerosis in vivo. Successful Completion of the proposed studies will unravel a novel mechanism underlying Olfm2 function in atherogenesis, which may ultimately lead to the development of therapeutic strategies against atherosclerosis in Veterans and general populations.