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Endothelial NO synthase as a source of NO and superoxide

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Abstract

Endothelial nitric oxide (NO) synthase (eNOS) is responsible for most of the vascular NO produced. A functional eNOS transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) via flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) in the carboxy-terminal reductase domain to the heme in the amino-terminal oxygenase domain where the substrate L-arginine is oxidized to L-citrulline and NO. This normal flow of electrons requires dimerization of the enzyme, the presence of the substrate L-arginine, and presence of the 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 (ROS) in the vascular wall. NADPH oxidases represent major sources of this ROS and have been found upregulated in animal models of hypertension, diabetes, and sedentary lifestyle. Superoxide avidly interacts with vascular NO to form peroxynitrite (ONOO−). BH4 is highly sensitive to oxidation, e.g., by ONOO−, and reduced levels of BH4 promote eNOS uncoupling. In fact, in many cases, supplementation with BH4 is capable of correcting eNOS dysfunction. Alternatively, an oxidation of the zinc-thiolate complex of eNOS by ONOO− has been proposed as a mechanism for eNOS uncoupling. Under uncoupled conditions, superoxide is generated from the oxygenase domain of eNOS. eNOS uncoupling and its change from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models and in animals with cardiovascular pathophysiology such as spontaneously hypertensive rats (SHR), angiotensin-II-induced hypertension, or diabetes. Taken together, several mechanisms seem to underlie endothelial dysfunction, but an uncoupled eNOS markedly contributes to this phenomenon.

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  1. Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, 55101, Mainz, Germany

    Ulrich Förstermann

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Förstermann, U. Endothelial NO synthase as a source of NO and superoxide. Eur J Clin Pharmacol 62 (Suppl 1), 5–12 (2006). https://doi.org/10.1007/s00228-005-0006-x

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