Oxidant stress—a major cause of reduced endothelial nitric oxide availability in cardiovascular disease

Abstract

Common conditions predisposing to atherosclerosis, such as dyslipidemia, hypertension, diabetes, and smoking, are associated with increased vascular production of reactive oxygen species (ROS). One of the major consequences of increased vascular ROS production is a reduction of endothelial nitric oxide (NO) bioavailability. Importantly, endothelial NO not only produces endothelium-dependent vasodilation but also has potent antiatherogenic properties, including inhibition of platelet aggregation and adhesion molecule expression. This concept has been supported by several recent clinical studies, suggesting a close association of impaired endothelium-dependent vasomotion and clinical cardiovascular events. Increased vascular ROS production reduces endothelial NO not only by direct inactivation, but also as a consequence of increased oxidation of tetrahydrobiopterin and inhibition of dimethylarginine dimethylaminohydrolase. This may in part explain the profound impact of increased endothelial oxidant stress on endothelial NO bioactivity. An increased activity of NAD(P)H oxidase, a major vascular oxidant enzyme system, has been observed in both experimental atherosclerosis and human coronary disease and likely represents an important source of ROS. Moreover, NAD(P)H oxidase has been shown to cause endothelial NO synthase “uncoupling” and to promote xanthine oxidase-dependent superoxide production. In addition, in human coronary disease a reduced vascular activity of the antioxidant enzyme extracellular superoxide dismutase has been observed. Notably, cardiovascular treatment strategies such as statin, angiotensin-converting enzyme (ACE) inhibitor, and angiotensin I receptor blocker treatment may exert potent “antioxidant” effects by reducing NAD(P)H oxidase and increasing extracellular superoxide dismutase activity, leading to improved endothelial function. Restoring endothelial function has become an attractive therapeutic target, given accumulating observations supporting a prognostic role of endothelial dysfunction.