2013 Russell Ross Memorial Lecture in Vascular Biology

Abstract

Adults with diabetes are much more likely to suffer from cardiovascular disease than those without diabetes. Genetically engineered mouse models have started to provide important insight into the mechanisms whereby diabetes promotes atherosclerosis. Such models have demonstrated that diabetes promotes formation of atherosclerotic lesions, progression of lesions into advanced hemorrhaged lesions, and that it prevents lesion regression. The pro-atherosclerotic effects of diabetes are driven in part by the altered function of myeloid cells. The protein S100A9 and the receptor for advanced glycation end-products are important mediators of the effect of diabetes on myelopoiesis. 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-induced lesion initiation. The protective effects of S100A9-deficiency and myeloid ACSL1-deficiency in diabetic mice, but not in non-diabetic mice, indicate that myeloid cells are activated by diabetes through mechanisms that play minor roles in the absence of diabetes. The roles reactive oxygen species and insulin resistance in diabetes-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 will be paramount.

Clinical Update: Cardiovascular Disease in Diabetes Mellitus

“…23 A commonly used pre-clinical diabetes model involves streptozotocin-treatment, 45,46 which is toxic to pancreatic β-cells, in an atherosclerosis-prone animal such as an LDL-receptor or apo-E deficient mouse. 47 Hyperglycemia results in atherosclerotic lesion formation which can be prevented by intensive insulin therapy, 48 while accelerated atherosclerosis develops in the setting of hypercholesterolemia.…”

“…40,61–68 People with insulin resistance have higher rates of hypertension, dyslipidemia, and impaired glucose tolerance, 65,67,69,70 which contribute to development, progression, and complexity of atherosclerosis. Impairment of insulin signaling at multiple points in the insulin signaling pathway in endothelial cells, 71–77 VSMC 44,78–80 and macrophages 22,23,58 promotes development and progression of atherosclerosis, as does the proinflammatory state induced in insulin resistance (Figure 2). 22,23,81 …”

“…Impairment of insulin signaling at multiple points in the insulin signaling pathway in endothelial cells, 71–77 VSMC 44,78–80 and macrophages 22,23,58 promotes development and progression of atherosclerosis, as does the proinflammatory state induced in insulin resistance (Figure 2). 22,23,81 …”

“…Impaired insulin signaling has complex effects in macrophages, depending on the macrophage sub-type. 23,96–98 Multiple additional inflammatory signaling pathways may be activated with insulin resistance and may also stimulate atherosclerotic processes. 79,99–101 (Figure 2)…”

“…These mechanisms operate in a feed forward cycle, promoting atherosclerotic lesion progression within the inflammatory milieu. 22,23,58 Atherosclerotic lesions contain T-cells in addition to macrophages, but T-cells from individuals with diabetes have been found to have a predominance of the pro-inflammatory Th-1 phenotype. 23 In addition to deleterious effects of low density lipoprotein on macrophage and foam cells, cholesterol crystals themselves within the atherosclerotic lesion can activate the NACHT, LRR and PYD domains-containing protein 3 inflammasome complex.…”