Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction

Abstract

D iabetes 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 endothelial dysfunction in diabetes mellitus. Endothelial Function and Cardiovascular Health Endothelial Function and Vascular HomeostasisOriginally considered to be simply a physical barrier between the blood and vascular wall, the endothelium is now recognized as the most important component of normal vascular homeostasis, because it serves to maintain the anticoagulant, antiplatelet, and fibrinolytic phenotypes of vascular cells.The maintenance of vascular homeostasis is accomplished through the release of numerous dilator and constrictor substances (the endothelium is regarded as a complex endocrine and paracrine organ 4 ; Figure 1).The most important factor released by the endothelium is nitric oxide (NO), originally identified as endothelium-derived relaxing factor.Other endothelium-derived vasodilators include prostacyclin, bradykinin, and an uncharacterized endothelium-derived hyperpolarizing factor.Prostacyclin acts synergistically with NO to inhibit platelet aggregation.Bradykinin stimulates release of NO, prostacyclin, and endothelium-derived hyperpolarizing factor to inhibit platelet aggregation.Bradykinin also stimulates production of tissue plasminogen activator and thus may play an important role in fibrinolysis.The endothelium also produces vasoconstrictor substances such as endothelin (the most potent endogenous vasoconstrictor identified to date), reactive oxygen species (ROS), prostaglandin H 2 (PGH 2 ), thromboxane A 2 (TXA 2 ), and angiotensin II.Angiotensin II is not only a vasoconstrictor but also a pro-oxidant that stimulates production of endothelin.Endothelin and angiotensin II promote proliferation of smooth muscle cells and in this way contribute to plaque formation.Large amounts of endothelin are produced by activated macrophages and vascular smooth muscle cells, the cellular components of atherosclerotic plaques.Because the endothelium plays a key role in vascular homeostasis, damage to this cellular layer will upset the balance between vasoconstriction and vasodilation, initiating a number of events/processes that promote or exacerbate atherosclerosis.These include endothelial permeabilization, platelet aggregation, leukocyte adhesion, and cytokine production. Assays of Endothelial Function in the ClinicAn improved understanding of the vascular biology of the endothelium and appreciation of the central role of the