Endothelial Dysfunction in Hypercholesterolemia: Mechanisms, Pathophysiological Importance, and Therapeutic Interventions

Since the demonstration of the obligatory role of the endothelium in arterial relaxation by Furchgott and Zawadzki (1980), there has been great interest in the role of the endothelium in vascular disease. Apart from endothelium-dependent vasodilation, other important functions of the endothelium have now been studied, that is, the regulation of adhesion and infiltration of leukocytes and inhibition of platelet adhesion and aggregation. Many functions of the endothelium are influenced by nitric oxide (NO), which is synthesized by endothelial NO synthase. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. Multiple factors contribute to this, including increased inactivation of NO by radicals and inhibition of NO formation by different mechanisms. The functional implications of endothelial dysfunction are not completely defined. However, recent studies suggest that endothelial dysfunction contributes to myocardial perfusion abnormalities. Furthermore, endothelial dysfunction may play an important role with respect to development and progression of atherosclerosis because the endothelium is involved in the regulation of key events of the atherosclerotic process. Endothelial dysfunction in hypercholesterolemia is reversible by cholesterol-lowering treatment, that is treatment with HMG-CoA-reductase inhibitors. First experimental data suggest that maneuvers that increase the bioavailability of NO in hypercholesterolemia may even result in regression of preexisting atherosclerotic lesions.