Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure

Abstract

Time for primary review 26 days. Soon after the discovery of EDRF (endothelium derived relaxins factor) it became apparent that certain diseases are associated with an impairment of endothelium dependent vasorelaxation. In hypercholesterolemic rabbits and monkeys, vasorelaxation to acetylcholine is almost absent (Fig. 1) or changed into vasoconstriction [1,2]. Similar observations have been made in patients with coronary artery disease [3,4] or risk factors predisposing to atherosclerosis [5]. Likewise, endothelium-dependent vasorelaxation is abnormal in disease states such as heart failure, diabetes and hypertension [6]. In almost all of these disorders, there is a loss of endothelial production and/or bioavailability of NO (nitric oxide, nitrogen monoxide). This alteration of vascular function has been termed ‘endothelial dysfunction’ in the scientific literature. Although this term is widely used, it is quite imprecise. ‘Endothelial dysfunction’ may refer to impairments of important endothelial functions other than vasodilation, including anticoagulant and anti-inflammatory properties of the endothelium [7,8]. Nevertheless, ‘endothelial dysfunction’ has become widely used, and in fact, loss of nitric oxide in these conditions may contribute to alterations of other aspects of vascular function. The mechanisms underlying altered endothelium-dependent vascular relaxation in various disease states are almost certainly multifactorial, and seem to be dependent on the specific pathological condition, its duration, and the vascular bed being studied. Treatment with l-arginine or tetrahydrobiopterin has improved NO-mediated vasodilation in some instances, suggesting that there may be a deficiency of either the substrate for the enzyme NO synthase or one of its critical co-factors. Alterations of endothelial cell signaling may impair appropriate activation of the NO synthase in response to neurohumoral or mechanical stimuli. In very advanced atherosclerosis, expression of NO synthase in the endothelium declines, almost certainly reducing endothelium-dependent vascular relaxation. Finally, there is substantial evidence that in certain disease conditions, NO production is not altered, but its bioavailability is reduced because of oxidative inactivation by excessive production of the superoxide anion (O2−) in the vascular wall. Evidence for this phenomenon has been found in such diverse conditions such as hypercholesterolemia, atherosclerosis, hypertension, diabetes, heart failure, and cigarette smoking. The purpose of this review is to examine the mechanisms whereby vascular cells produce excessive reactive oxygen species (and in particular superoxide), to consider cellular and molecular mechanisms underlying their reactions with NO, and to discuss the effects of reactive oxygen species on vascular diseases.