Endothelial dysfunction in normal and abnormal glucose metabolism.

Abstract

The endothelium is the common target of all cardiovascular risk factors, and functional impairment of the vascular endothelium in response to injury occurs long before the development of visible atherosclerosis. The endothelial cell behaves as a receptor-effector structure which senses different physical or chemical stimuli that occur inside the vessel and, therefore, modifies the vessel shape or releases the necessary products to counteract the effect of the stimulus and maintain homeostasis. The endothelium is capable of producing a large variety of different molecules which act as agonists and antagonists, therefore balancing their effects in opposite directions. When endothelial cells lose their ability to maintain this delicate balance, the conditions are given for the endothelium to be invaded by lipids and leukocytes (monocytes and T lymphocytes). The inflammatory response is incited and fatty streaks appear, the first step in the formation of the atheromatous plaque. If the situation persists, fatty streaks progress and the resultant plaques are exposed to rupture and set the conditions for thrombogenesis and vascular occlusion. Oxidant products are produced as a consequence of normal aerobic metabolism. These molecules are highly reactive with other biological molecules and are referred as reactive oxygen species (ROS). Under normal physiological conditions, ROS production is balanced by an efficient system of antioxidants, molecules that are capable of neutralizing them and thereby preventing oxidant damage. In pathological states, ROS may be present in relative excess. This shift of balance in favor of oxidation, termed 'oxidative stress', may have detrimental effects on cellular and tissue function, and cardiovascular risk factors generate oxidative stress. Both type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients have mostly been described under enhanced oxidative stress, and both conditions are known to be powerful and independent risk factors for coronary heart disease, stroke, and peripheral arterial disease. Hyperglycemia causes glycosylation of proteins and phospholipids, thus increasing intracellular oxidative stress. Nonenzymatic reactive products, glucose-derived Schiff base, and Amadori products form chemically reversible early glycosylation products which subsequently rearrange to form more stable products, some of them long-lived proteins (collagen) which continue undergoing complex series of chemical rearrangements to form advanced glycosylation end products (AGEs). Once formed, AGEs are stable and virtually irreversible. AGEs generate ROS with consequent increased vessel oxidative damage and atherogenesis. The impressive correlation between coronary artery disease and alterations in glucose metabolism has raised the hypothesis that atherosclerosis and diabetes may share common antecedents. Large-vessel atherosclerosis can precede the development of diabetes, suggesting that rather than atherosclerosis being a complication of diabetes, both conditions may share genetic and environmental antecedents, a 'common soil'.