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2004 | 51 | 2 | 459-469
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Endothelial NADH/NADPH-dependent enzymatic sources of superoxide production: relationship to endothelial dysfunction.

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There is growing evidence that endothelial dysfunction, which is often defined as the decreased endothelial-derived nitric oxide (NO) bioavailability, is a crucial factor leading to vascular disease states such as hypertension, diabetes, atherosclerosis, heart failure and cigarette smoking. This is due to the fact that the lack of NO in endothelium-dependent vascular disorders contributes to impaired vascular relaxation, platelet aggregation, increased vascular smooth muscle proliferation, and enhanced leukocyte adhesion to the endothelium. During the last several years, it has become clear that reduction of NO bioavailability in the endothelium-impaired function disorders is associated with an increase in endothelial production of superoxide (O2̇̄). Because O2̇̄ rapidly scavenges NO within the endothelium, a reduction of bioactive NO might occur despite an increased NO generation. Among many enzymatic systems that are capable of producing O2̇̄, NAD(P)H oxidase and uncoupled endothelial NO synthase (eNOS) apparently are the main sources of O2̇̄ in the endothelial cells. It seems that O2̇̄ generated by NAD(P)H oxidase may trigger eNOS uncoupling and contribute to the endothelial balance between NO and O2̇̄. That is maintained at diverse levels.
Physical description
  • Department of Clinical Chemistry and Laboratory of Cellular and Molecular Nephrology, Medical Research Centre of the Polish Academy of Science, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, U.S.A.
  • Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature.; 351: 714-8.
  • Brunner F, Wolkart G, Pfeiffer S, Russell JC, Wascher TC. (2000) Vascular dysfunction and myocardial contractility in the JCR:LA-corpulent rat. Cardiovasc Res.; 47: 150-8.
  • Cahilly C, Ballantyne CM, Lim DS, Gotto A, Marian AJ. (2000) A variant of p22(phox), involved in generation of reactive oxygen species in the vessel wall, is associated with progression of coronary atherosclerosis. Circ Res.; 86: 391-5.
  • Cai H, Harrison DG. (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res.; 87: 840-4.
  • Channon KM, Qian H, George SE. (2000) Nitric oxide synthase in atherosclerosis and vascular injury: insights from experimental gene therapy. Arterioscler Thromb Vasc Biol.; 20: 1873-81.
  • Cheng JW, Baldwin SN, Balwin SN. (2001) L-arginine in the management of cardiovascular diseases. Ann Pharmacother.; 35: 755-64.
  • Cooke JP, Dzau VJ. (1997) Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med.; 48: 489-509.
  • Cosentino F, Patton S, d'Uscio LV, Werner ER, Werner-Felmayer G, Moreau P, Malinski T, Luscher TF. (1998) Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats. J Clin Invest.; 101: 1530-7.
  • De Keulenaer GW, Alexander RW, Ushio-Fukai M, Ishizaka N, Griendling KK. (1998) Tumour necrosis factor alpha activates a p22phox-based NADH oxidase in vascular smooth muscle. Biochem J.; 329 (Pt 3): 653-7.
  • De Vriese AS, Stoenoiu MS, Elger M, Devuyst O, Vanholder R, Kriz W, Lameire NH. (2001) Diabetes-induced microvascular dysfunction in the hydronephrotic kidney: role of nitric oxide. Kidney Int.; 60: 202-10.
  • Dixon LJ, Morgan DR, Hughes SM, McGrath LT, El-Sherbeeny NA, Plumb RD, Devine A, Leahey W, Johnston GD, McVeigh GE. (2003) Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Circulation.; 107: 1725-8.
  • Dupont GP, Huecksteadt TP, Marshall BC, Ryan US, Michael JR, Hoidal JR. (1992) Regulation of xanthine dehydrogenase and xanthine oxidase activity and gene expression in cultured rat pulmonary endothelial cells. J Clin Invest.; 89: 197-202.
  • Fenster BE, Tsao PS, Rockson SG. (2003) Endothelial dysfunction: clinical strategies for treating oxidant stress. Am Heart J.; 146: 218-26.
  • Gewaltig MT, Kojda G. (2002) Vasoprotection by nitric oxide: mechanisms and therapeutic potential. Cardiovasc Res.; 55: 250-60.
  • Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. (1994) Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res.; 74: 1141-8.
  • Griendling KK, Sorescu D, Ushio-Fukai M. (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res.; 86: 494-501.
  • Guzik TJ, West NE, Black E, McDonald D, Ratnatunga C, Pillai R, Channon KM. (2000) Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res.; 86: E85-90.
  • Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, Channon KM. (2002) Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation.; 105: 1656-62.
  • Hamilton CA, Brosnan MJ, Al-Benna S, Berg G, Dominiczak AF. (2002) NAD(P)H oxidase inhibition improves endothelial function in rat and human blood vessels. Hypertension.; 40: 755-62.
  • Hamilton CA, Miller WH, Al-Benna S, Brosnan MJ, Drummond RD, McBride MW, Dominiczak AF. (2004) Strategies to reduce oxidative stress in cardiovascular disease. Clin Sci (London).; 106: 219-34.
  • Harrison DG. (1997) Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest.; 100: 2153-7.
  • Heitzer T, Brockhoff C, Mayer B, Warnholtz A, Mollnau H, Henne S, Meinertz T, Munzel T. (2000a) Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase. Circ Res.; 86: E36-41.
  • Heitzer T, Krohn K, Albers S, Meinertz T. (2000b) Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus. Diabetologia.; 43: 1435-8.
  • Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation.; 104: 2673-8.
  • Hemmens B, Mayer B. (1998) Enzymology of nitric oxide synthases. Methods Mol Biol.; 100: 1-32.
  • Houston M, Estevez A, Chumley P, Aslan M, Marklund S, Parks DA, Freeman BA. (1999) Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling. J Biol Chem.; 274: 4985-94.
  • Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature.; 377: 239-42.
  • Huie RE, Padmaja S. (1993) The reaction of NO with superoxide. Free Radic Res Commun.; 18: 195-9.
  • Huk I, Nanobashvili J, Neumayer C, Punz A, Mueller M, Afkhampour K, Mittlboeck M, Losert U, Polterauer P, Roth E, Patton S, Malinski T. (1997) L-arginine treatment alters the kinetics of nitric oxide and superoxide release and reduces ischemia/reperfusion injury in skeletal muscle. Circulation.; 96: 667-75.
  • Jessup W. (1996) Oxidized lipoproteins and nitric oxide. Curr Opin Lipidol.; 7: 274-80.
  • Jin N, Packer CS, Rhoades RA. (1991) Reactive oxygen-mediated contraction in pulmonary arterial smooth muscle: cellular mechanisms. Can J Physiol Pharmacol.; 69: 383-8.
  • Kalinowski L, Dobrucki IT, Malinski T. (2004) Race-specific differences in endothelial function: predisposition of African Americans to vascular diseases. Circulation.; 109: 2511-7.
  • Kerr S, Brosnan MJ, McIntyre M, Reid JL, Dominiczak AF, Hamilton CA. (1999) Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium. Hypertension.; 33: 1353-8.
  • Kinoshita H, Katusic ZS. (1996) Exogenous tetrahydrobiopterin causes endothelium-dependent contractions in isolated canine basilar artery. Am J Physiol.; 271: H738-43.
  • Klatt P, Heinzel B, Mayer B, Ambach E, Werner-Felmayer G, Wachter H, Werner ER. (1992) Stimulation of human nitric oxide synthase by tetrahydrobiopterin and selective binding of the cofactor. FEBS Lett.; 305: 160-2.
  • Landmesser U, Harrison DG. (2001) Oxidative stress and vascular damage in hypertension. Coron Artery Dis.; 12: 455-61.
  • Liao JK, Shin WS, Lee WY, Clark SL. (1995) Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem.; 270: 319-24.
  • Mayer B, Heinzel B, Klatt P, John M, Schmidt K, Bohme E. (1992) Nitric oxide synthase-catalyzed activation of oxygen and reduction of cytochromes: reaction mechanisms and possible physiological implications. J Cardiovasc Pharmacol.; 20 (Suppl 12): S54-6.
  • Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz M, August M, Kleschyov AL, Tsilimingas N, Walter U, Forstermann U, Meinertz T, Griendling K, Munzel T. (2002) Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res.; 90: E58-65.
  • Moroi M, Zhang L, Yasuda T, Virmani R, Gold HK, Fishman MC, Huang PL. (1998) Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest.; 101: 1225-32.
  • Munzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG. (1995) Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest.; 95: 187-94.
  • Munzel T, Li H, Mollnau H, Hink U, Matheis E, Hartmann M, Oelze M, Skatchkov M, Warnholtz A, Duncker L, Meinertz T, Forstermann U. (2000) Effects of long-term nitroglycerin treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS III-mediated superoxide production, and vascular NO bioavailability. Circ Res.; 86: E7-E12.
  • Nakazono K, Watanabe N, Matsuno K, Sasaki J, Sato T, Inoue M. (1991) Does superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci USA.; 88: 10045-8.
  • Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Luscher TF. (1998) Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation.; 97: 2494-8.
  • Ohara Y, Peterson TE, Harrison DG. (1993) Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest.; 91: 2546-51.
  • Palmer RM, Ashton DS, Moncada S. (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature.; 333: 664-6.
  • Pieper GM. (1997) Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol.; 29: 8-15.
  • Pritchard KA Jr, Groszek L, Smalley DM, Sessa WC, Wu M, Villalon P, Wolin MS, Stemerman MB. (1995) Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res.; 77: 510-8.
  • Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest.; 97: 1916-23.
  • Raman CS, Li H, Martasek P, Kral V, Masters BS, Poulos TL. (1998) Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Cell.; 95: 939-50.
  • Rouquette M, Page S, Bryant R, Benboubetra M, Stevens CR, Blake DR, Whish WD, Harrison R, Tosh D. (1998) Xanthine oxidoreductase is asymmetrically localised on the outer surface of human endothelial and epithelial cells in culture. FEBS Lett.; 426: 397-401.
  • Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. (1998) Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest.; 101: 731-6.
  • Rueckschloss U, Galle J, Holtz J, Zerkowski HR, Morawietz H. (2001) Induction of NAD(P)H oxidase by oxidized low-density lipoprotein in human endothelial cells: antioxidative potential of hydroxymethylglutaryl coenzyme A reductase inhibitor therapy. Circulation.; 104: 1767-72.
  • Sanders SA, Eisenthal R, Harrison R. (1997) NADH oxidase activity of human xanthine oxidoreductase-generation of superoxide anion. Eur J Biochem.; 245: 541-8.
  • Schachinger V, Britten MB, Zeiher AM. (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation.; 101: 1899-906.
  • Schachinger V, Britten MB, Dimmeler S, Zeiher AM. (2001) NADH/NADPH oxidase p22 phox gene polymorphism is associated with improved coronary endothelial vasodilator function. Eur Heart J.; 22: 96-101.
  • Schulz E, Tsilimingas N, Rinze R, Reiter B, Wendt M, Oelze M, Woelken-Weckmuller S, Walter U, Reichenspurner H, Meinertz T, Munzel T. (2002) Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. Circulation.; 105: 1170-5.
  • Setoguchi S, Mohri M, Shimokawa H, Takeshita A. (2001) Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease. J Am Coll Cardiol.; 38: 493-8.
  • Shinozaki K, Nishio Y, Okamura T, Yoshida Y, Maegawa H, Kojima H, Masada M, Toda N, Kikkawa R, Kashiwagi A. (2000) Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ Res.; 87: 566-73.
  • Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Luscher T, Rabelink T. (1997) Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest.; 99: 41-6.
  • Stroes E, Hijmering M, van Zandvoort M, Wever R, Rabelink TJ, van Faassen EE. (1998) Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett.; 438: 161-4.
  • Suzuki YJ, Ford GD. (1992) Superoxide stimulates IP3-induced Ca2+ release from vascular smooth muscle sarcoplasmic reticulum. Am J Physiol.; 262: H114-6.
  • Suzuki H, Swei A, Zweifach BW, Schmid-Schonbein GW. (1995) In vivo evidence for microvascular oxidative stress in spontaneously hypertensive rats. Hydroethidine microfluorography. Hypertension.; 25: 1083-9.
  • Sydow K, Munzel T. (2003) ADMA and oxidative stress. Atheroscler (Suppl).; 4: 41-51.
  • Tarpey MM. (2002) Sepiapterin treatment in atherosclerosis. Arterioscler Thromb Vasc Biol.; 22: 1519-21.
  • Tiefenbacher CP, Chilian WM, Mitchell M, DeFily DV. (1996) Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin. Circulation.; 94: 1423-9.
  • Toutouzas PC, Tousoulis D, Davies GJ. (1998) Nitric oxide synthesis in atherosclerosis. Eur Heart J.; 19: 1504-11.
  • Tsutsui M, Milstien S, Katusic ZS. (1996) Effect of tetrahydrobiopterin on endothelial function in canine middle cerebral arteries. Circ Res.; 79: 336-42.
  • van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Luscher TF. (2000) Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med.; 192: 1731-44.
  • Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr. (1998) Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA.; 95: 9220-5.
  • Vasquez-Vivar J, Duquaine D, Whitsett J, Kalyanaraman B, Rajagopalan S. (2002) Altered tetrahydrobiopterin metabolism in atherosclerosis: implications for use of oxidized tetrahydrobiopterin analogues and thiol antioxidants. Arterioscler Thromb Vasc Biol.; 22: 1655-61.
  • Verma S, Lovren F, Dumont AS, Mather KJ, Maitland A, Kieser TM, Triggle CR, Anderson TJ. (2000) Tetrahydrobiopterin improves endothelial function in human saphenous veins. J Thorac Cardiovasc Surg.; 120: 668-71.
  • Verma S, Maitland A, Weisel RD, Fedak PW, Pomroy NC, Li SH, Mickle DA, Li RK, Rao V. (2002) Novel cardioprotective effects of tetrahydrobiopterin after anoxia and reoxygenation: Identifying cellular targets for pharmacologic manipulation. J Thorac Cardiovasc Surg.; 123: 1074-83.
  • Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. (1990) Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation.; 81: 491-7.
  • Wever RM, van Dam T, van Rijn HJ, de Groot F, Rabelink TJ. (1997) Tetrahydrobiopterin regulates superoxide and nitric oxide generation by recombinant endothelial nitric oxide synthase. Biochem Biophys Res Commun.; 237: 340-4.
  • White KA, Marletta MA. (1992) Nitric oxide synthase is a cytochrome P-450 type hemoprotein. Biochemistry.; 31: 6627-31.
  • White CR, Darley-Usmar V, Berrington WR, McAdams M, Gore JZ, Thompson JA, Parks DA, Tarpey MM, Freeman BA. (1996) Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits. Proc Natl Acad Sci USA.; 93: 8745-9.
  • Wolin MS. (2000) Interactions of oxidants with vascular signaling systems. Arterioscler Thromb Vasc Biol.; 20: 1430-42.
  • Zembowicz A, Tang JL, Wu KK. (1995) Transcriptional induction of endothelial nitric oxide synthase type III by lysophosphatidylcholine. J Biol Chem.; 270: 17006-10.
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