Cellular and Molecular Mechanisms of Diabetes-Accelerated Atherosclerosis

Abstract

I will be very honored to present the 2013 Russell Ross Memorial Lecture in Vascular Biology. I will discuss our current understanding of the cellular and molecular mechanisms whereby diabetes accelerates atherosclerosis, based on data primarily from mouse models. Diabetes accelerates the formation of atherosclerotic lesions in hyperglycemic mouse models in which plasma lipid levels are unaltered by diabetes. Diabetes-accelerated lesion formation is driven, at least in part, by the altered function and properties of myeloid cells; cells that contribute to an increased inflammatory vascular state. Based on our recent studies, the enzyme acyl-CoA synthetase 1 (ACSL1), which converts long-chain fatty acids into their acyl-CoA derivatives, has emerged as causal to the enhanced lesion initiation associated with diabetes. ACSL1 is expressed at higher levels in monocytes/macrophages from diabetic mice and humans, as compared to controls, and is induced by inflammatory mediators in these cells. Interestingly, the protective effect of myeloid ACSL1-deficiency is obvious in diabetic mice, but not in non-diabetic mice, indicating that ACSL1-deficiency targets a pathway that is selectively activated by diabetes. Diabetes also accelerates progression of atherosclerotic lesions to advanced plaques characterized by hemorrhage. This effect is dependent on diabetes-induced dyslipidemia. Important questions for future research are whether ACSL1 and other factors identified in mouse models play equally important roles in diabetes-accelerated atherosclerosis and cardiovascular disease in humans.