2013 Russell Ross memorial lecture in vascular biology: cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis

Abstract

Adults with diabetes mellitus are much more likely to have cardiovascular disease than those without diabetes mellitus. Genetically engineered mouse models have started to provide important insight into the mechanisms whereby diabetes mellitus promotes atherosclerosis. Such models have demonstrated that diabetes mellitus promotes formation of atherosclerotic lesions, progression of lesions into advanced hemorrhaged lesions, and that it prevents lesion regression. The proatherosclerotic effects of diabetes mellitus are driven in part by the altered function of myeloid cells. The protein S100A9 and the receptor for advanced glycation end-products are important modulators of the effect of diabetes mellitus on myelopoiesis, which might promote monocyte accumulation in lesions. Furthermore, myeloid cell expression of the enzyme acyl-CoA synthetase 1 (ACSL1), which converts long-chain fatty acids into their acyl-CoA derivatives, has emerged as causal to diabetes mellitus-induced lesion initiation. The protective effects of myeloid ACSL1-deficiency in diabetic mice, but not in nondiabetic mice, indicate that myeloid cells are activated by diabetes mellitus through mechanisms that play minor roles in the absence of diabetes mellitus. The roles of reactive oxygen species and insulin resistance in diabetes mellitus-accelerated atherosclerosis are also discussed, primarily in relation to endothelial cells. Translational studies addressing whether the mechanisms identified in mouse models are equally important in humans with diabetes mellitus will be paramount.

Keywords: atherosclerosis; diabetes mellitus; endothelial cells; macrophages; mice.

Figure 1. Diabetes-accelerated atherosclerosis: what we have learnt and some important remaining questions

A. Diabetes accelerates initiation of early macrophage-rich lesions. This lesion from a diabetic Ldlr^−/−;Gp^Tg mouse demonstrates macrophage accumulation (indicated by an asterisk) and glycosaminoglycan accumulation in the media (turquoise stain indicated by a white arrow). B. Diabetes causes progression and increased intraplaque haemorrhage in the macrophage-rich shoulder regions of more advanced lesions in diabetic Ldlr^−/−;Gp^Tg mice. Intraplaque haemorrhage is seen as an intense red stain and is indicated by white stars. C. Diabetes hinders regression of lesions of atherosclerosis. This advanced lesion exhibits large necrotic cores (indicated by black stars), macrophage-rich areas (indicated by asterisk), and SMCs (indicated by black squares), some of which are located in fibrous caps. Regression models have demonstrated that at least the macrophage-rich areas can regress, albeit less efficiently ion diabetic mice. Effects of diabetes on the different stages of atherosclerosis are mediated by pro-atherosclerotic changes in endothelial cells and myeloid cells. Although the past few years have provided important insight into the mechanisms of diabetes-accelerated atherosclerosis in mouse models, several questions remain. Some of these are listed in the figure. Scale bar = 100 µm. Panel A is reproduced from Renard et al. with permission of the Journal of Clinical Investigation and the American Society for Clinical Investigation. Panel B is reproduced from Johansson et al.; Copyright (2008) National Academy of Sciences, U.S.A.