Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction

Diabetes mellitus and its associated complications are major health problems in the developed world. Diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) even in the presence of intensive glycemic control. Indeed, 75% of diabetic patients will die of CVD. Patients with type 1 and type 2 diabetes mellitus have an increased risk for the 3 major types of macrovascular disease (coronary heart disease, peripheral vascular disease, and stroke).1 A striking feature of diabetic cardiovascular complications is the appearance of accelerated atherosclerosis, which anatomically resembles atherosclerosis in nondiabetic individuals but is more extensive and occurs at an earlier age. Substantial clinical and experimental evidence suggests that endothelial dysfunction is a crucial early step in the development of atherosclerosis. Evidence also suggests that it participates in plaque progression and the clinical emergence of cardiovascular events. Endothelial dysfunction is characterized by impaired endothelium-dependent vasodilation and “endothelial activation,” which is associated with a proinflammatory, proliferative, and procoagulatory milieu that promotes initiation and complications of atherogenesis.2 Endothelial dysfunction associated with insulin resistance appears to precede the development of overt hyperglycemia in patients with type 2 diabetes mellitus.3 Therefore, endothelial dysfunction may be a critical early target for the prevention of atherosclerosis and CVD in patients with diabetes mellitus or insulin resistance.2 A synergistic cross talk exists among the conventional cardiovascular risk factors associated with diabetes mellitus, and such cross talk contributes to disruption of endothelial integrity and acceleration of atherosclerosis. However, the biochemical and cellular links between elevated blood glucose levels and endothelial dysfunction remain incompletely understood. This review will focus on the multifactorial nature of endothelial dysfunction in diabetes mellitus, the relationship between endothelial dysfunction and conventional cardiovascular risk factors, and the translational potential of molecular targets such as the AMP-activated protein kinase (AMPK) for treating …