Endothelial nitric oxide synthase in vascular disease -: From marvel to menace

Nitric oxide (NO center dot) is an important protective molecule in the vasculature, and endothelial NO center dot synthase (eNOS) is responsible for most of the vascular NO center dot produced. A functional eNOS oxidizes its substrate L-arginine to L-citrulline and NO center dot. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate L-arginine, and the essential cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O-2(center dot-)) reacts avidly with vascular NO center dot to form peroxynitrite (ONOO-). The cofactor BH4 is highly sensitive to oxidation by ONOO-. Diminished levels of BH4 promote O-2(center dot-) production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH4 has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH4 levels as well.