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(Circulation. 2006;113:1708-1714.)
© 2006 American Heart Association, Inc.

Basic Science for Clinicians

Endothelial Nitric Oxide Synthase in Vascular Disease

From Marvel to Menace

Ulrich Förstermann, MD, PhD; Thomas Münzel, MD

From the Departments of Pharmacology (U.F.) and Internal Medicine II (Cardiology) (T.M.), Johannes Gutenberg University Hospitals, Mainz, Germany.

Correspondence to Ulrich Förstermann, MD, PhD, Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. E-mail ulrich.forstermann{at}uni-mainz.de

Nitric oxide (NO·) is an important protective molecule in the vasculature, and endothelial NO· synthase (eNOS) is responsible for most of the vascular NO· produced. A functional eNOS oxidizes its substrate L-arginine to L-citrulline and NO·. 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 (O₂·^–) reacts avidly with vascular NO· to form peroxynitrite (ONOO^–). The cofactor BH₄ is highly sensitive to oxidation by ONOO^–. Diminished levels of BH₄ promote O₂·^– 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.

Key Words: endothelium • arteriosclerosis • endothelium-derived factors • nitric oxide synthase • risk factors

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				J. Yang, C. B. Ambrosone, C.-C. Hong, J. Ahn, C. Rodriguez, M. J. Thun, and E. E. Calle Relationships between polymorphisms in NOS3 and MPO genes, cigarette smoking and risk of post-menopausal breast cancer Carcinogenesis, June 1, 2007; 28(6): 1247 - 1253. [Abstract] [Full Text] [PDF]

				X. Gao, X. Xu, S. Belmadani, Y. Park, Z. Tang, A. M. Feldman, W. M. Chilian, and C. Zhang TNF-{alpha} Contributes to Endothelial Dysfunction by Upregulating Arginase in Ischemia/Reperfusion Injury Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1269 - 1275. [Abstract] [Full Text] [PDF]

				L. A. Holowatz and W. L. Kenney Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans J. Physiol., June 1, 2007; 581(2): 863 - 872. [Abstract] [Full Text] [PDF]

				H. Viswambharan, J. M. Carvas, V. Antic, A. Marecic, C. Jud, C. E. Zaugg, X.-F. Ming, J.-P. Montani, U. Albrecht, and Z. Yang Mutation of the Circadian Clock Gene Per2 Alters Vascular Endothelial Function Circulation, April 24, 2007; 115(16): 2188 - 2195. [Abstract] [Full Text] [PDF]

				S. Horke, I. Witte, P. Wilgenbus, M. Kruger, D. Strand, and U. Forstermann Paraoxonase-2 Reduces Oxidative Stress in Vascular Cells and Decreases Endoplasmic Reticulum Stress-Induced Caspase Activation Circulation, April 17, 2007; 115(15): 2055 - 2064. [Abstract] [Full Text] [PDF]

				J. E. Deanfield, J. P. Halcox, and T. J. Rabelink Endothelial Function and Dysfunction: Testing and Clinical Relevance Circulation, March 13, 2007; 115(10): 1285 - 1295. [Full Text] [PDF]

				T. Thum, D. Fraccarollo, M. Schultheiss, S. Froese, P. Galuppo, J. D. Widder, D. Tsikas, G. Ertl, and J. Bauersachs Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes Diabetes, March 1, 2007; 56(3): 666 - 674. [Abstract] [Full Text] [PDF]

				L. J. Ignarro, M. L. Balestrieri, and C. Napoli Nutrition, physical activity, and cardiovascular disease: An update Cardiovasc Res, January 15, 2007; 73(2): 326 - 340. [Abstract] [Full Text] [PDF]

				T. M.C. Brunini, A. C. Mendes-Ribeiro, J. C. Ellory, and G. E. Mann Platelet nitric oxide synthesis in uremia and malnutrition: A role for L-arginine supplementation in vascular protection? Cardiovasc Res, January 15, 2007; 73(2): 359 - 367. [Abstract] [Full Text] [PDF]

				D. E. Berkowitz Myocyte Nitroso-Redox Imbalance in Sepsis: NO Simple Answer Circ. Res., January 5, 2007; 100(1): 1 - 4. [Full Text] [PDF]

				A. Drouin, N. Thorin-Trescases, E. Hamel, J. R. Falck, and E. Thorin Endothelial nitric oxide synthase activation leads to dilatory H2O2 production in mouse cerebral arteries Cardiovasc Res, January 1, 2007; 73(1): 73 - 81. [Abstract] [Full Text] [PDF]

				A. Nohria, M. E. Grunert, Y. Rikitake, K. Noma, A. Prsic, P. Ganz, J. K. Liao, and M. A. Creager Rho Kinase Inhibition Improves Endothelial Function in Human Subjects With Coronary Artery Disease Circ. Res., December 8, 2006; 99(12): 1426 - 1432. [Abstract] [Full Text] [PDF]

				S. Ryoo, C. A. Lemmon, K. G. Soucy, G. Gupta, A. R. White, D. Nyhan, A. Shoukas, L. H. Romer, and D. E. Berkowitz Oxidized Low-Density Lipoprotein-Dependent Endothelial Arginase II Activation Contributes to Impaired Nitric Oxide Signaling Circ. Res., October 27, 2006; 99(9): 951 - 960. [Abstract] [Full Text] [PDF]

				H. J. Zhao, S. Wang, H. Cheng, M.-z. Zhang, T. Takahashi, A. B. Fogo, M. D. Breyer, and R. C. Harris Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2664 - 2669. [Abstract] [Full Text] [PDF]

				S. Ryoo, L. Santhanam, D. Nyhan, and D. E. Berkowitz Response to Does Arginase Activity In Vitro Represent That In Vivo? Hypertension, October 1, 2006; 48(4): E15 - E15. [Full Text] [PDF]

				J. Bauersachs and D. Fraccarollo Endothelial NO Synthase Target of Aldosterone Hypertension, July 1, 2006; 48(1): 27 - 28. [Full Text] [PDF]