This Article Full Text Full Text (PDF) All Versions of this Article: 26/2/267    most recent 01.ATV.0000196554.85799.77v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rabelink, T. J. Articles by Luscher, T. F. Search for Related Content PubMed PubMed Citation Articles by Rabelink, T. J. Articles by Luscher, T. F. Related Collections Endothelium/vascular type/nitric oxide Pathophysiology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:267.)
© 2006 American Heart Association, Inc.

Brief Reviews

Endothelial Nitric Oxide Synthase

Host Defense Enzyme of the Endothelium?

Ton J. Rabelink; Thomas F. Luscher

From the Department of Nephrology and Hypertension (T.J.R.), Leiden University Medical Center, The Netherlands; and the Department of Cardiology (T.F.L.), University Hospital Zurich, Switzerland.

Correspondence to Ton J. Rabelink, Department of Nephrology and Hypertension, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail t.rabelink{at}lumc.nl

This article explores the physiology of superoxide generation by endothelial nitric oxide synthase (eNOS), the so-called "uncoupled" state of the enzyme. The fact that this alternative chemistry of the eNOS enzyme is evolutionary strongly conserved, suggests that it may play a physiological role. It is proposed that this uncoupled state may contribute to defense against infections. As the switch from NO production to reactive oxygen species by eNOS is also the final common pathway in atherogenesis, the uncoupling of eNOS further builds on the hypothesis that atherogenesis is driven by cellular mechanisms that originally serve host defense. The central role of uncoupled eNOS in redox signaling in the endothelium may open up new avenues for therapy to prevent atherosclerosis.

This article explores the physiology of superoxide generation by endothelial nitric oxide synthase, the so-called "uncoupled" state of the enzyme. The fact that this alternative chemistry of the eNOS enzyme is evolutionary strongly conserved, suggests that it may play a physiological role. It is proposed that this uncoupled state may contribute to defense against infections, and the central role of uncoupled eNOS in redox signaling in the endothelium may open up new avenues for therapy to prevent atherosclerosis.

Key Words: endothelium • nitric oxide • atherosclerosis

This article has been cited by other articles:

				S. Ryoo, G. Gupta, A. Benjo, H. K. Lim, A. Camara, G. Sikka, H. K. Lim, J. Sohi, L. Santhanam, K. Soucy, et al. Endothelial Arginase II: A Novel Target for the Treatment of Atherosclerosis Circ. Res., April 25, 2008; 102(8): 923 - 932. [Abstract] [Full Text] [PDF]

				G. Li, J.-P. del Rincon, L. A. Jahn, Y. Wu, B. Gaylinn, M. O. Thorner, and Z. Liu Growth Hormone Exerts Acute Vascular Effects Independent of Systemic or Muscle Insulin-like Growth Factor I J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1379 - 1385. [Abstract] [Full Text] [PDF]

				V. W.T. Liu and P. L. Huang Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted mice Cardiovasc Res, January 1, 2008; 77(1): 19 - 29. [Abstract] [Full Text] [PDF]

				R. K. Upmacis, M. J. Crabtree, R. S. Deeb, H. Shen, P. B. Lane, L. E. S. Benguigui, N. Maeda, D. P. Hajjar, and S. S. Gross Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2878 - H2887. [Abstract] [Full Text] [PDF]

				G. Li, E. J. Barrett, M. O. Barrett, W. Cao, and Z. Liu Tumor Necrosis Factor-{alpha} Induces Insulin Resistance in Endothelial Cells via a p38 Mitogen-Activated Protein Kinase-Dependent Pathway Endocrinology, July 1, 2007; 148(7): 3356 - 3363. [Abstract] [Full Text] [PDF]

				J.-P. Stasch, P.M. Schmidt, P.I. Nedvetsky, T.Y. A. Nedvetskaya, H.S. Kumar, S. Meurer, M. Deile, A. Taye, A. Knorr, H. Lapp, et al. Endothelial Cell Dysfunction--Can One Outsmart Oxidative Stress by Direct Interaction with the Pathological Oxidized or Heme-Free Soluble Guanyl-Cyclase?: Targeting the Heme-Oxydized Nitric Oxide Receptor for Selective Vasodilatation of Diseased Blood Vessels. J Clin Invest 116: 2552-2561, 2006 J. Am. Soc. Nephrol., March 1, 2007; 18(3): 663 - 669. [Full Text] [PDF]

				M. Simionescu Implications of Early Structural-Functional Changes in the Endothelium for Vascular Disease Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 266 - 274. [Abstract] [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]

				T. J. Rabelink and A.-J. van Zonneveld Coupling eNOS Uncoupling to the Innate Immune Response. Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2585 - 2587. [Full Text] [PDF]

				W. S. Waring, J. A. McKnight, D. J. Webb, and S. R.J. Maxwell Uric Acid Restores Endothelial Function in Patients With Type 1 Diabetes and Regular Smokers Diabetes, November 1, 2006; 55(11): 3127 - 3132. [Abstract] [Full Text] [PDF]