Abstract 455: The Effects of Diet on Occlusive Coronary Artery Atherosclerosis, Thrombosis and Myocardial Infarction in SR-BI/LDL Receptor Double KO Mice

abstract

Objective: Deficiency of the HDL receptor, SR-BI, in apolipoprotein E knockout or hypomorphic mice respectively results in spontaneous or diet-inducible occlusive coronary artery atherosclerosis, myocardial infarction, and early death. Here, we examine the effects of SR-BI deficiency on cardiovascular phenotypes in LDLR knockout mice fed different atherogenic diets. Approach and Results SR-BI/LDLR double knockout and control LDLR knockout mice were fed diets containing different amounts of fat and cholesterol and which either lacked or contained 0.5% sodium cholate. Double knockout mice fed diets high in cholesterol exhibited significantly reduced survival compared to LDLR knockout mice fed the same diets. In addition to increased aortic sinus atherosclerosis, we observed significant coronary artery atherosclerosis in double knockout mice, and diet dependent accumulation of platelets in coronary artery atherosclerotic plaques. This was accompanied by substantial myocardial fibrosis in double knockout mice fed high cholesterol diets. Double knockout mice also exhibited higher circulating cytokine levels, monocytosis with increased proportions of monocytes expressing high levels of Ly6C, and higher adhesion molecule expression in coronary artery endothelial cells compared to control LDLR knockout mice. Conclusions: Diet accelerated atherosclerosis and occlusive, platelet rich coronary artery disease in SR-BI/LDLR dKO mice is affected by amounts of cholesterol and cholate in atherogenic diets, and is accompanied by increased expression of VCAM-1 and ICAM-1 in coronary arteries and increased Ly6C+ monocytes in circulation. The increased VCAM-1 and ICAM-1 in coronary artery endothelial cells in SR-BI-deficient mice likely explains their increased susceptibility to atherosclerosis in coronary arteries.