Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis.

Type 2 diabetes is associated with a two to fourfold increased risk of both coronary heart disease and stroke. Dysfunction of endothelial cells (EC) is known to promote abnormal vascular growth such as that in atherosclerosis and arteriosclerosis and has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes mellitus, and hyperglycemia is an independent risk factor for the development of cardiovascular disease. We and others have previously demonstrated that high D-glucose induced apoptosis through activation of the bax-caspase proteases pathway in human EC and the potential contribution of hepatocyte growth factor, as an anti-apoptotic factor, to the pathogenesis of endothelial dysfunction. The anti-apoptotic action of HGF was due to bcl-2-upregulation and the phosphatidylinositol 3-kinase pathway, which is involved in Akt activation. Although it has been known for years that cardiovascular tissues can release a large amount ROS, including superoxide, hydrogen peroxide, and nitric oxide, the role of oxidative stress in atherogenesis has received increasing attention in recent years. Recent work strongly suggests that NADPH oxidase is a major source of superoxide in cardiovascular cells, and oxidative stress can be involved in the process of endothelial dysfunction. NADPH oxidase can be activated in hyperglycemia through the protein kinase C pathway. From the viewpoint of these molecular mechanisms, HMG-CoA reductase inhibitors (statins) might inhibit the high glucose-induced NADPH oxidase activation through inhibition of Rac activity and finally prevent the increase in ROS production in diabetes. A recent clinical trial suggested that statins prevent several vascular events in patients with type 2 diabetes without a high concentration of LDL-cholesterol. These pleiotropic effects of statins can be expected to improve endothelial dysfunction through nitric oxide production and/or an anti-oxidant effect in diabetic patients.