Mechanisms of hyperglycemia-induced foam cell formation and atherosclerosis in type-2 diabetes. Role of the hexosamine biosynthetic pathway

Vascular disease is the most common cause of death in people suffering from type 2 diabetes. The high risk of atherosclerotic disease in type 2 diabetes can in part be accounted for by the diabetic state per se, such as hyperglycemia. Uptake of oxidised LDL and accumulation of cholesterol esters in monocyte/macrophages (foam cell formation) is an important early event in atherosclerosis. We have shown that hyperglycemia in combination with insulin or leptin, significantly increased the rate of cholestero l ester deposition in macrophages. This was accompanied by a down-regulation of neutral cholesterol esterase activity, and reduced expression of Hormone-sensitive lipase, as well as an up-regulation of acyl-CoA-cholesterol-acyltransferase activity. We w ere therefore interested in identifying molecules that are regulated by hyperglycemia in macrophages. By a gene array approach, weidentified several genes, of which the most interesting candidate was the transcriptional repressor, Id2. Most notably, we fo und that hyperglycemia up-regulates Id2 protein expression via the hexosamine biosynthetic pathway. The objective of the present project is to understand the mechanisms by which hyperglycemia via the hexosamine biosynthetic pathway promotes macrophage foa m cell formation with particular interest in the role of Id2 in this process. Also, we want to elucidate the effect of hyperglycaemia on T-cell activation as T-cells infiltrate atherosclerotic lesions promoting activation of macrophages and initiate infla mmatory responses through the production of interferon-gamma. Results from this project will potentially help to identify targets for drug intervention to prevent the progression of atherosclerosis in patients with type-2 diabetes by inhibiting proteins responsible for glucose-induced cholesterol ester accumulation in macrophages.