Nitric oxide and oxidative stress in vascular disease

Invited Review

Abstract

Endothelium-derived nitric oxide (NO) is a paracrine factor that controls vascular tone, inhibits platelet function, prevents adhesion of leukocytes, and reduces proliferation of the intima. An enhanced inactivation and/or reduced synthesis of NO is seen in conjunction with risk factors for cardiovascular disease. This condition, referred to as endothelial dysfunction, can promote vasospasm, thrombosis, vascular inflammation, and proliferation of vascular smooth muscle cells. Vascular oxidative stress with an increased production of reactive oxygen species (ROS) contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase, or the mitochondrial respiratory chain) and anti-oxidative enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase, and paraoxonase) in favor of the former. Also, small molecular weight antioxidants may play a role in the defense against oxidative stress. Increased ROS concentrations reduce the amount of bioactive NO by chemical inactivation to form toxic peroxynitrite. Peroxynitrite—in turn—can “uncouple” endothelial NO synthase to become a dysfunctional superoxide-generating enzyme that contributes to vascular oxidative stress. Oxidative stress and endothelial dysfunction can promote atherogenesis. Therapeutically, drugs in clinical use such as ACE inhibitors, AT1 receptor blockers, and statins have pleiotropic actions that can improve endothelial function. Also, dietary polyphenolic antioxidants can reduce oxidative stress, whereas clinical trials with antioxidant vitamins C and E failed to show an improved cardiovascular outcome.

Keywords

Endothelial NO synthase Reactive oxygen species AT1 receptor antagonists ACE inhibitors Statins Vitamin C Vitamin E Polyphenols 

References

  1. 1.
    Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615PubMedCrossRefGoogle Scholar
  2. 2.
    Arts IC, Hollman PC (2005) Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 81:317S–325SPubMedGoogle Scholar
  3. 3.
    Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN (1998) Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest 101:1581–1590PubMedCrossRefGoogle Scholar
  4. 4.
    Bachetti T, Comini L, Francolini G, Bastianon D, Valetti B, Cadei M, Grigolato P, Suzuki H, Finazzi D, Albertini A, Curello S, Ferrari R (2004) Arginase pathway in human endothelial cells in pathophysiological conditions. J Mol Cell Cardiol 37:515–523PubMedCrossRefGoogle Scholar
  5. 5.
    Ballinger SW, Patterson C, Knight-Lozano CA, Burow DL, Conklin CA, Hu Z, Reuf J, Horaist C, Lebovitz R, Hunter GC, McIntyre K, Runge MS (2002) Mitochondrial integrity and function in atherogenesis. Circulation 106:544–549PubMedCrossRefGoogle Scholar
  6. 6.
    Barry-Lane PA, Patterson C, van der Merwe M, Hu Z, Holland SM, Yeh ET, Runge MS (2001) p47phox is required for atherosclerotic lesion progression in ApoE(−/−) mice. J Clin Invest 108:1513–1522PubMedGoogle Scholar
  7. 7.
    Bec N, Gorren AFC, Mayer B, Schmidt PP, Andersson KK, Lange R (2000) The role of tetrahydrobiopterin in the activation of oxygen by nitric-oxide synthase. J Inorg Biochem 81:207–211PubMedCrossRefGoogle Scholar
  8. 8.
    Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM (2003) Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 108:2000–2006PubMedCrossRefGoogle Scholar
  9. 9.
    Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ, Champion HC (2001) Increased expression of arginase II in human diabetic corpus cavernosum: in diabetic-associated erectile dysfunction. Biochem Biophys Res Commun 283:923–927PubMedCrossRefGoogle Scholar
  10. 10.
    Blankenberg S, Rupprecht HJ, Bickel C, Torzewski M, Hafner G, Tiret L, Smieja M, Cambien F, Meyer J, Lackner KJ (2003) Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N Engl J Med 349:1605–1613PubMedCrossRefGoogle Scholar
  11. 11.
    Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Boger SM (2000) LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 87:99–105PubMedGoogle Scholar
  12. 12.
    Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL (2004) Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 351:2058–2068PubMedCrossRefGoogle Scholar
  13. 13.
    Buga GM, Singh R, Pervin S, Rogers NE, Schmitz DA, Jenkinson CP, Cederbaum SD, Ignarro LJ (1996) Arginase activity in endothelial cells: inhibition by NG-hydroxy-l-arginine during high-output NO production. Am J Physiol 271:H1988–H1998PubMedGoogle Scholar
  14. 14.
    Butler R, Morris AD, Belch JJ, Hill A, Struthers AD (2000) Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35:746–751PubMedGoogle Scholar
  15. 15.
    Cardillo C, Kilcoyne CM, Cannon RO 3rd, Quyyumi AA, Panza JA (1997) Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension 30:57–63PubMedGoogle Scholar
  16. 16.
    Closs EI, Scheld JS, Sharafi M, Forstermann U (2000) Substrate supply for nitric-oxide synthase in macrophages and endothelial cells: role of cationic amino acid transporters. Mol Pharmacol 57:68–74PubMedGoogle Scholar
  17. 17.
    Cosentino F, Katusic ZS (1995) Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 91:139–144PubMedGoogle Scholar
  18. 18.
    Cosentino F, Luscher TF (1998) Tetrahydrobiopterin and endothelial function. Eur Heart J 19(Suppl G):G3–G8PubMedGoogle Scholar
  19. 19.
    Crane BR, Arvai AS, Ghosh DK, Wu C, Getzoff ED, Stuehr DJ, Tainer JA (1998) Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science 279:2121–2126PubMedCrossRefGoogle Scholar
  20. 20.
    Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ (1996) Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation 94:2756–2767PubMedGoogle Scholar
  21. 21.
    Dikalova A, Clempus R, Lassegue B, Cheng G, McCoy J, Dikalov S, San Martin A, Lyle A, Weber DS, Weiss D, Taylor WR, Schmidt HH, Owens GK, Lambeth JD, Griendling KK (2005) Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice. Circulation 112:2668–2676PubMedCrossRefGoogle Scholar
  22. 22.
    Drexler H, Zeiher AM, Meinzer K, Just H (1991) Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by l-arginine. Lancet 338:1546–1550PubMedCrossRefGoogle Scholar
  23. 23.
    Drummond GR, Cai H, Davis ME, Ramasamy S, Harrison DG (2000) Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res 86:347–354PubMedGoogle Scholar
  24. 24.
    Ellis GR, Anderson RA, Lang D, Blackman DJ, Morris RH, Morris-Thurgood J, McDowell IF, Jackson SK, Lewis MJ, Frenneaux MP (2000) Neutrophil superoxide anion-generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy. J Am Coll Cardiol 36:1474–1482PubMedCrossRefGoogle Scholar
  25. 25.
    Fleming I, Busse R (2003) Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 284:R1–R12PubMedGoogle Scholar
  26. 26.
    Förstermann U (2008) Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 5:338–349PubMedCrossRefGoogle Scholar
  27. 27.
    Förstermann U, Münzel T (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113:1708–1714PubMedCrossRefGoogle Scholar
  28. 28.
    Förstermann U, Nakane M, Tracey WR, Pollock JS (1993) Isoforms of nitric oxide synthase: functions in the cardiovascular system. Eur Heart J 14(Suppl I):10–15PubMedGoogle Scholar
  29. 29.
    Fox KM (2003) Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 362:782–788PubMedCrossRefGoogle Scholar
  30. 30.
    Fukuda Y, Teragawa H, Matsuda K, Yamagata T, Matsuura H, Chayama K (2002) Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia. Heart 87:264–269PubMedCrossRefGoogle Scholar
  31. 31.
    Fukui T, Ishizaka N, Rajagopalan S, Laursen JB, Qt C, Taylor WR, Harrison DG, de Leon H, Wilcox JN, Griendling KK (1997) p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res 80:45–51PubMedGoogle Scholar
  32. 32.
    Gokce N, Keaney JF Jr, Frei B, Holbrook M, Olesiak M, Zachariah BJ, Leeuwenburgh C, Heinecke JW, Vita JA (1999) Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 99:3234–3240PubMedGoogle Scholar
  33. 33.
    Gorren AC, Kungl AJ, Schmidt K, Werner ER, Mayer B (2001) Electrochemistry of pterin cofactors and inhibitors of nitric oxide synthase. Nitric Oxide 5:176–186PubMedCrossRefGoogle Scholar
  34. 34.
    Gorren AC, List BM, Schrammel A, Pitters E, Hemmens B, Werner ER, Schmidt K, Mayer B (1996) Tetrahydrobiopterin-free neuronal nitric oxide synthase: evidence for two identical highly anticooperative pteridine binding sites. Biochemistry 35:16735–16745PubMedCrossRefGoogle Scholar
  35. 35.
    Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86:494–501PubMedGoogle Scholar
  36. 36.
    Grote K, Flach I, Luchtefeld M, Akin E, Holland SM, Drexler H, Schieffer B (2003) Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species. Circ Res 92:e80–e86PubMedCrossRefGoogle Scholar
  37. 37.
    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 105:1656–1662PubMedCrossRefGoogle Scholar
  38. 38.
    Hecker M, Sessa WC, Harris HJ, Anggard EE, Vane JR (1990) The metabolism of l-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle l-citrulline to l-arginine. Proc Natl Acad Sci U S A 87:8612–8616PubMedCrossRefGoogle Scholar
  39. 39.
    Hein TW, Zhang C, Wang W, Chang CI, Thengchaisri N, Kuo L (2003) Ischemia–reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J 17:2328–2330PubMedGoogle Scholar
  40. 40.
    Heinzel B, John M, Klatt P, Bohme E, Mayer B (1992) Ca2+/calmodulin-dependent formation of hydrogen peroxide by brain nitric oxide synthase. Biochem J 281(Pt 3):627–630PubMedGoogle Scholar
  41. 41.
    Heitzer T, Krohn K, Albers S, Meinertz T (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia 43:1435–1438PubMedCrossRefGoogle Scholar
  42. 42.
    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 104:2673–2678PubMedCrossRefGoogle Scholar
  43. 43.
    Heitzer T, Brockhoff C, Mayer B, Warnholtz A, Mollnau H, Henne S, Meinertz T, Munzel T (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: evidence for a dysfunctional nitric oxide synthase. Circ Res 86:E36–E41PubMedGoogle Scholar
  44. 44.
    Heller R, Werner-Felmayer G, Werner ER (2006) Antioxidants and endothelial nitric oxide synthesis. Eur J Clin Pharmacol 62(Suppl 13):21–28CrossRefGoogle Scholar
  45. 45.
    Hemmens B, Mayer B (1998) Enzymology of nitric oxide synthases. Methods Mol Biol 100:1–32PubMedGoogle Scholar
  46. 46.
    Hemmens B, Goessler W, Schmidt K, Mayer B (2000) Role of bound zinc in dimer stabilization but not enzyme activity of neuronal nitric-oxide synthase. J Biol Chem 275:35786–35791PubMedCrossRefGoogle Scholar
  47. 47.
    Higashi Y, Sasaki S, Nakagawa K, Fukuda Y, Matsuura H, Oshima T, Chayama K (2002) Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals. Am J Hypertens 15:326–332PubMedCrossRefGoogle Scholar
  48. 48.
    Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88:E14–E22PubMedGoogle Scholar
  49. 49.
    Hishikawa K, Nakaki T, Suzuki H, Kato R, Saruta T (1993) Role of l-arginine nitric oxide pathway in hypertension. J Hypertension 11:639–645CrossRefGoogle Scholar
  50. 50.
    Ho YS, Xiong Y, Ma W, Spector A, Ho DS (2004) Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J Biol Chem 279:32804–32812PubMedCrossRefGoogle Scholar
  51. 51.
    Hoekstra KA, Godin DV, Cheng KM (2004) Protective role of heme oxygenase in the blood vessel wall during atherogenesis. Biochem Cell Biol 82:351–359PubMedCrossRefGoogle Scholar
  52. 52.
    Hong H-J, Hsiao G, Cheng T-H, Yen M-H (2001) Supplementation with tetrahydrobiopterin suppresses the development of hypertension in spontaneously hypertensive rats. Hypertension 38:1044–1048PubMedCrossRefGoogle Scholar
  53. 53.
    Horke S, Witte I, Wilgenbus P, Kruger M, Strand D, Forstermann U (2007) Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation. Circulation 115:2055–2064PubMedCrossRefGoogle Scholar
  54. 54.
    Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A, Tatge H, Drexler H (2001) Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 103:799–805PubMedGoogle Scholar
  55. 55.
    Iida S, Chu Y, Weiss RM, Kang YM, Faraci FM, Heistad DD (2006) Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure. Am J Physiol Heart Circ Physiol 291:H914–H920PubMedCrossRefGoogle Scholar
  56. 56.
    Imaizumi T, Hirooka Y, Masaki H, Harada S, Momohara M, Tagawa T, Takeshita A (1992) Effects of l-arginine on forearm vessels and responses to acetylcholine. Hypertension 20:511–517PubMedGoogle Scholar
  57. 57.
    Jiang F, Roberts SJ, Datla S, Dusting GJ (2006) NO modulates NADPH oxidase function via heme oxygenase-1 in human endothelial cells. Hypertension 48:950–957PubMedCrossRefGoogle Scholar
  58. 58.
    Johnson FK, Johnson RA, Peyton KJ, Durante W (2005) Arginase inhibition restores arteriolar endothelial function in Dahl rats with salt-induced hypertension. Am J Physiol Regul Integr Comp Physiol 288:R1057–R1062PubMedGoogle Scholar
  59. 59.
    Jung O, Marklund SL, Xia N, Busse R, Brandes RP (2007) Inactivation of extracellular superoxide dismutase contributes to the development of high-volume hypertension. Arterioscler Thromb Vasc Biol 27:470–477PubMedCrossRefGoogle Scholar
  60. 60.
    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 33:1353–1358PubMedGoogle Scholar
  61. 61.
    Klingbeil AU, John S, Schneider MP, Jacobi J, Handrock R, Schmieder RE (2003) Effect of AT1 receptor blockade on endothelial function in essential hypertension. Am J Hypertens 16:123–128PubMedCrossRefGoogle Scholar
  62. 62.
    Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K (2000) The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6:1004–1010PubMedCrossRefGoogle Scholar
  63. 63.
    Kuzkaya N, Weissmann N, Harrison DG, Dikalov S (2003) Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem 278:22546–22554PubMedCrossRefGoogle Scholar
  64. 64.
    Landmesser U, Merten R, Spiekermann S, Buttner K, Drexler H, Hornig B (2000) Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 101:2264–2270PubMedGoogle Scholar
  65. 65.
    Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, Holland SM, Harrison DG (2002) Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40:511–515PubMedCrossRefGoogle Scholar
  66. 66.
    Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111:1201–1209PubMedGoogle Scholar
  67. 67.
    Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S, Manes C, Fischer D, de Groot K, Fliser D, Fauler G, Marz W, Drexler H (2005) Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 111:2356–2363PubMedCrossRefGoogle Scholar
  68. 68.
    Laufs U, La Fata V, Plutzky J, Liao JK (1998) Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97:1129–1135PubMedGoogle Scholar
  69. 69.
    Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA, Tarpey M, Fukai T, Harrison DG (2001) Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 103:1282–1288PubMedGoogle Scholar
  70. 70.
    Leus FR, Zwart M, Kastelein JJ, Voorbij HA (2001) PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients. Atherosclerosis 154:641–649PubMedCrossRefGoogle Scholar
  71. 71.
    Li H, Forstermann U (2009) Resveratrol: a multifunctional compound improving endothelial function. Editorial to: “Resveratrol supplementation gender independently improves endothelial reactivity and suppresses superoxide production in healthy rats” by S. Soylemez et al. Cardiovasc Drugs Ther 23:425–429PubMedCrossRefGoogle Scholar
  72. 72.
    Li H, Wallerath T, Munzel T, Forstermann U (2002) Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. Nitric Oxide 7:149–164PubMedCrossRefGoogle Scholar
  73. 73.
    Li H, Raman CS, Glaser CB, Blasko E, Young TA, Parkinson JF, Whitlow M, Poulos TL (1999) Crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase. Implications for dimer stability and comparison with endothelial nitric-oxide synthase. J Biol Chem 274:21276–21284PubMedCrossRefGoogle Scholar
  74. 74.
    Li H, Oehrlein SA, Wallerath T, Ihrig-Biedert I, Wohlfart P, Ulshofer T, Jessen T, Herget T, Forstermann U, Kleinert H (1998) Activation of protein kinase C alpha and/or epsilon enhances transcription of the human endothelial nitric oxide synthase gene. Mol Pharmacol 53:630–637PubMedGoogle Scholar
  75. 75.
    Li H, Witte K, August M, Brausch I, Godtel-Armbrust U, Habermeier A, Closs EI, Oelze M, Munzel T, Forstermann U (2006) Reversal of endothelial nitric oxide synthase uncoupling and up-regulation of endothelial nitric oxide synthase expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol 47:2536–2544PubMedCrossRefGoogle Scholar
  76. 76.
    Li H, Witte K, August M, Brausch I, Gödtel-Armbrust U, Habermeier A, Closs EI, Oelze M, Münzel T, Förstermann U (2006) Reversal of eNOS uncoupling and upregulation of eNOS expression lowers blood pressure in hypertensive rats. J Amer Coll Cardiol 47:2536–2544CrossRefGoogle Scholar
  77. 77.
    Liao JK (2002) Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol 86:5–18PubMedCrossRefGoogle Scholar
  78. 78.
    Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106:987–992PubMedCrossRefGoogle Scholar
  79. 79.
    Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais GR (2005) Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. Jama 293:1338–1347PubMedCrossRefGoogle Scholar
  80. 80.
    Manach C, Mazur A, Scalbert A (2005) Polyphenols and prevention of cardiovascular diseases. Curr Opin Lipidol 16:77–84PubMedCrossRefGoogle Scholar
  81. 81.
    Martasek P, Miller RT, Liu Q, Roman LJ, Salerno JC, Migita CT, Raman CS, Gross SS, Ikeda-Saito M, Masters BS (1998) The C331A mutant of neuronal nitric-oxide synthase is defective in arginine binding. J Biol Chem 273:34799–34805PubMedCrossRefGoogle Scholar
  82. 82.
    Masters BS, McMillan K, Sheta EA, Nishimura JS, Roman LJ, Martasek P (1996) Neuronal nitric oxide synthase, a modular enzyme formed by convergent evolution: structure studies of a cysteine thiolate-liganded heme protein that hydroxylates l-arginine to produce NO. as a cellular signal. FASEB J 10:552–558PubMedGoogle Scholar
  83. 83.
    Matsuno K, Yamada H, Iwata K, Jin D, Katsuyama M, Matsuki M, Takai S, Yamanishi K, Miyazaki M, Matsubara H, Yabe-Nishimura C (2005) Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation 112:2677–2685PubMedCrossRefGoogle Scholar
  84. 84.
    McNally JS, Davis ME, Giddens DP, Saha A, Hwang J, Dikalov S, Jo H, Harrison DG (2003) Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol 285:H2290–H2297PubMedGoogle Scholar
  85. 85.
    Miller RT, Martasek P, Omura T, Siler Masters BS (1999) Rapid kinetic studies of electron transfer in the three isoforms of nitric oxide synthase. Biochem Biophys Res Commun 265:184–188PubMedCrossRefGoogle Scholar
  86. 86.
    Miller RT, Martasek P, Raman CS, Masters BS (1999) Zinc content of Escherichia coli-expressed constitutive isoforms of nitric-oxide synthase. Enzymatic activity and effect of pterin. J Biol Chem 274:14537–14540PubMedCrossRefGoogle Scholar
  87. 87.
    Milstien S, Katusic Z (1999) Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Biochem Biophys Res Commun 263:681–684PubMedCrossRefGoogle Scholar
  88. 88.
    Ming XF, Barandier C, Viswambharan H, Kwak BR, Mach F, Mazzolai L, Hayoz D, Ruffieux J, Rusconi S, Montani JP, Yang Z (2004) Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation 110:3708–3714PubMedCrossRefGoogle Scholar
  89. 89.
    Moat SJ, Clarke ZL, Madhavan AK, Lewis MJ, Lang D (2006) Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis. Eur J Pharmacol 530:250–258PubMedCrossRefGoogle Scholar
  90. 90.
    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–E65PubMedCrossRefGoogle Scholar
  91. 91.
    Morita T (2005) Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 25:1786–1795PubMedCrossRefGoogle Scholar
  92. 92.
    Mueller CF, Laude K, McNally JS, Harrison DG (2005) Redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol 25:274–278PubMedCrossRefGoogle Scholar
  93. 93.
    Ng CJ, Bourquard N, Grijalva V, Hama S, Shih DM, Navab M, Fogelman AM, Lusis AJ, Young S, Reddy ST (2006) Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2. J Biol Chem 281:29491–29500PubMedCrossRefGoogle Scholar
  94. 94.
    Nickenig G, Harrison DG (2002) The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis. Circulation 105:393–396PubMedCrossRefGoogle Scholar
  95. 95.
    Nickenig G, Baumer AT, Temur Y, Kebben D, Jockenhovel F, Bohm M (1999) Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation 100:2131–2134PubMedGoogle Scholar
  96. 96.
    Noble MA, Munro AW, Rivers SL, Robledo L, Daff SN, Yellowlees LJ, Shimizu T, Sagami I, Guillemette JG, Chapman SK (1999) Potentiometric analysis of the flavin cofactors of neuronal nitric oxide synthase. Biochemistry 38:16413–16418PubMedCrossRefGoogle Scholar
  97. 97.
    O’Driscoll JG, Green DJ, Rankin JM, Taylor RR (1999) Nitric oxide-dependent endothelial function is unaffected by allopurinol in hypercholesterolaemic subjects. Clin Exp Pharmacol Physiol 26:779–783PubMedCrossRefGoogle Scholar
  98. 98.
    Ohara Y, Peterson TE, Harrison DG (1993) Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 91:2546–2551PubMedCrossRefGoogle Scholar
  99. 99.
    Ohashi M, Runge MS, Faraci FM, Heistad DD (2006) MnSOD deficiency increases endothelial dysfunction in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 26:2331–2336PubMedCrossRefGoogle Scholar
  100. 100.
    Ohishi M, Ueda M, Rakugi H, Naruko T, Kojima A, Okamura A, Higaki J, Ogihara T (1997) Enhanced expression of angiotensin-converting enzyme is associated with progression of coronary atherosclerosis in humans. J Hypertens 15:1295–1302PubMedCrossRefGoogle Scholar
  101. 101.
    Paolini M, Sapone A, Canistro D, Chieco P, Valgimigli L (2003) Antioxidant vitamins for prevention of cardiovascular disease. Lancet 362:920, author reply 921PubMedCrossRefGoogle Scholar
  102. 102.
    Pieper GM (1997) Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol 29:8–15PubMedCrossRefGoogle Scholar
  103. 103.
    Pollock JS, Forstermann U, Mitchell JA, Warner TD, Schmidt HH, Nakane M, Murad F (1991) Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci U S A 88:10480–10484PubMedCrossRefGoogle Scholar
  104. 104.
    Pou S, Keaton L, Surichamorn W, Rosen GM (1999) Mechanism of superoxide generation by neuronal nitric-oxide synthase. J Biol Chem 274:9573–9580PubMedCrossRefGoogle Scholar
  105. 105.
    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 77:510–518PubMedGoogle Scholar
  106. 106.
    Ramachandran A, Levonen AL, Brookes PS, Ceaser E, Shiva S, Barone MC, Darley-Usmar V (2002) Mitochondria, nitric oxide, and cardiovascular dysfunction. Free Radic Biol Med 33:1465–1474PubMedCrossRefGoogle Scholar
  107. 107.
    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 95:939–950PubMedCrossRefGoogle Scholar
  108. 108.
    Rosenkranz-Weiss P, Sessa WC, Milstien S, Kaufman S, Watson CA, Pober JS (1994) Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J Clin Invest 93:2236–2243PubMedCrossRefGoogle Scholar
  109. 109.
    Rossitch E, Alexander E, Black PM, Cooke JP (1991) l-arginine normalizes endothelial function in cerebral vessels from hypercholesterolemic rabbits. J Clin Invest 87:1295–1299PubMedCrossRefGoogle Scholar
  110. 110.
    Rozenberg O, Shih DM, Aviram M (2005) Paraoxonase 1 (PON1) attenuates macrophage oxidative status: studies in PON1 transfected cells and in PON1 transgenic mice. Atherosclerosis 181:9–18PubMedCrossRefGoogle Scholar
  111. 111.
    Schachinger V, Britten MB, Zeiher AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101:1899–1906PubMedGoogle Scholar
  112. 112.
    Shinozaki K, Kashiwagi A, Nishio Y, Okamura T, Yoshida Y, Masada M, Toda N, Kikkawa R (1999) Abnormal biopterin metabolism is a major cause of impaired endothelium- dependent relaxation through nitric oxide/O2- imbalance in insulin-resistant rat aorta. Diabetes 48:2437–2445PubMedCrossRefGoogle Scholar
  113. 113.
    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 87:566–573PubMedGoogle Scholar
  114. 114.
    Simon A, Plies L, Habermeier A, Martine U, Reining M, Closs EI (2003) Role of neutral amino acid transport and protein breakdown for substrate supply of nitric oxide synthase in human endothelial cells. Circ Res 93:813–820PubMedCrossRefGoogle Scholar
  115. 115.
    Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105:1429–1435PubMedCrossRefGoogle Scholar
  116. 116.
    Stanner SA, Hughes J, Kelly CN, Buttriss J (2004) A review of the epidemiological evidence for the ’antioxidant hypothesis’. Public Health Nutr 7:407–422PubMedCrossRefGoogle Scholar
  117. 117.
    Steinkamp-Fenske K, Bollinger L, Xu H, Yao Y, Horke S, Forstermann U, Li H (2007) Reciprocal regulation of endothelial nitric-oxide synthase and NADPH oxidase by betulinic acid in human endothelial cells. J Pharmacol Exp Ther 322:836–842PubMedCrossRefGoogle Scholar
  118. 118.
    Steinkamp-Fenske K, Bollinger L, Voller N, Xu H, Yao Y, Bauer R, Forstermann U, Li H (2007) Ursolic acid from the Chinese herb danshen (Salvia miltiorrhiza L.) upregulates eNOS and downregulates Nox4 expression in human endothelial cells. Atherosclerosis 195:e104–e111PubMedCrossRefGoogle Scholar
  119. 119.
    Stocker R, Perrella MA (2006) Heme oxygenase-1: a novel drug target for atherosclerotic diseases? Circulation 114:2178–2189PubMedCrossRefGoogle Scholar
  120. 120.
    Stoclet JC, Chataigneau T, Ndiaye M, Oak MH, El Bedoui J, Chataigneau M, Schini-Kerth VB (2004) Vascular protection by dietary polyphenols. Eur J Pharmacol 500:299–313PubMedCrossRefGoogle Scholar
  121. 121.
    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 99:41–46PubMedCrossRefGoogle Scholar
  122. 122.
    Stroes ES, van Faassen EE, Yo M, Martasek P, Boer P, Govers R, Rabelink TJ (2000) Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 86:1129–1134PubMedGoogle Scholar
  123. 123.
    Stuehr D, Pou S, Rosen GM (2001) Oxygen reduction by nitric-oxide synthases. J Biol Chem 276:14533–14536PubMedCrossRefGoogle Scholar
  124. 124.
    Sydow K, Munzel T (2003) ADMA and oxidative stress. Atheroscler Suppl 4:41–51PubMedCrossRefGoogle Scholar
  125. 125.
    Sydow K, Schwedhelm E, Arakawa N, Bode-Boger SM, Tsikas D, Hornig B, Frolich JC, Boger RH (2003) ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of l-arginine and B vitamins. Cardiovasc Res 57:244–252PubMedCrossRefGoogle Scholar
  126. 126.
    Taille C, El-Benna J, Lanone S, Dang MC, Ogier-Denis E, Aubier M, Boczkowski J (2004) Induction of heme oxygenase-1 inhibits NAD(P)H oxidase activity by down-regulating cytochrome b558 expression via the reduction of heme availability. J Biol Chem 279:28681–28688PubMedCrossRefGoogle Scholar
  127. 127.
    Torzewski M, Ochsenhirt V, Kleschyov AL, Oelze M, Daiber A, Li H, Rossmann H, Tsimikas S, Reifenberg K, Cheng F, Lehr HA, Blankenberg S, Forstermann U, Munzel T, Lackner KJ (2007) Deficiency of glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 27:850–857PubMedCrossRefGoogle Scholar
  128. 128.
    Touyz RM, Yao G, Schiffrin EL (2003) c-Src induces phosphorylation and translocation of p47phox: role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 23:981–987PubMedCrossRefGoogle Scholar
  129. 129.
    Turrens JF, Alexandre A, Lehninger AL (1985) Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 237:408–414PubMedCrossRefGoogle Scholar
  130. 130.
    Tward A, Xia YR, Wang XP, Shi YS, Park C, Castellani LW, Lusis AJ, Shih DM (2002) Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation 106:484–490PubMedCrossRefGoogle Scholar
  131. 131.
    van Etten RW, de Koning EJ, Honing ML, Stroes ES, Gaillard CA, Rabelink TJ (2002) Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 22:799–804PubMedCrossRefGoogle Scholar
  132. 132.
    Vaziri ND, Ni Z, Oveisi F (1998) Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats. Hypertension 31:1248–1254PubMedGoogle Scholar
  133. 133.
    Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G, Brovkovych V, Fellin R, Malinski T (2000) Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production: key role of l-arginine availability. Circulation 101:1261–1266PubMedGoogle Scholar
  134. 134.
    Verhaar MC, Stroes E, Rabelink TJ (2002) Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol 22:6–13PubMedCrossRefGoogle Scholar
  135. 135.
    Verhaar MC, Wever RM, Kastelein JJ, van Dam T, Koomans HA, Rabelink TJ (1998) 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 97:237–241PubMedGoogle Scholar
  136. 136.
    Vita JA (2005) Polyphenols and cardiovascular disease: effects on endothelial and platelet function. Am J Clin Nutr 81:292S–297SPubMedGoogle Scholar
  137. 137.
    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 81:491–497PubMedGoogle Scholar
  138. 138.
    Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M (2000) Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 20:61–69PubMedGoogle Scholar
  139. 139.
    Wallerath T, Poleo D, Li H, Forstermann U (2003) Red wine increases the expression of human endothelial nitric oxide synthase: a mechanism that may contribute to its beneficial cardiovascular effects. J Am Coll Cardiol 41:471–478PubMedCrossRefGoogle Scholar
  140. 140.
    Wallerath T, Li H, Godtel-Ambrust U, Schwarz PM, Forstermann U (2005) A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide 12:97–104PubMedCrossRefGoogle Scholar
  141. 141.
    Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, Forstermann U (2002) Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106:1652–1658PubMedCrossRefGoogle Scholar
  142. 142.
    Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Bohm M, Meinertz T, Munzel T (1999) Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin–angiotensin system. Circulation 99:2027–2033PubMedGoogle Scholar
  143. 143.
    Wassmann S, Laufs U, Baumer AT, Muller K, Konkol C, Sauer H, Bohm M, Nickenig G (2001) Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 59:646–654PubMedGoogle Scholar
  144. 144.
    Wassmann S, Laufs U, Baumer AT, Muller K, Ahlbory K, Linz W, Itter G, Rosen R, Bohm M, Nickenig G (2001) HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37:1450–1457PubMedGoogle Scholar
  145. 145.
    Werner ER, Gorren AC, Heller R, Werner-Felmayer G, Mayer B (2003) Tetrahydrobiopterin and nitric oxide: mechanistic and pharmacological aspects. Exp Biol Med 228:1291–1302Google Scholar
  146. 146.
    Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Schmidt K, Weiss G, Wachter H (1993) Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP. J Biol Chem 268:1842–1846PubMedGoogle Scholar
  147. 147.
    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 U S A 93:8745–8749PubMedCrossRefGoogle Scholar
  148. 148.
    Wilmink HW, Stroes ES, Erkelens WD, Gerritsen WB, Wever R, Banga JD, Rabelink TJ (2000) Influence of folic acid on postprandial endothelial dysfunction. Arterioscler Thromb Vasc Biol 20:185–188PubMedGoogle Scholar
  149. 149.
    Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS (1999) Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol 34:2002–2006PubMedCrossRefGoogle Scholar
  150. 150.
    Xia Y, Tsai AL, Berka V, Zweier JL (1998) Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem 273:25804–25808PubMedCrossRefGoogle Scholar
  151. 151.
    Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, Thunnissen FB, Farver C, Hazen SL, Jennings C, Dweik RA, Arroliga AC, Erzurum SC (2004) Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 18:1746–1748PubMedGoogle Scholar
  152. 152.
    Yamashiro S, Kuniyoshi Y, Arakaki K, Miyagi K, Koja K (2002) The effect of insufficiency of tetrahydrobiopterin on endothelial function and vasoactivity. Jpn J Thorac Cardiovasc Surg 50:472–477PubMedCrossRefGoogle Scholar
  153. 153.
    Yamawaki H, Haendeler J, Berk BC (2003) Thioredoxin: a key regulator of cardiovascular homeostasis. Circ Res 93:1029–1033PubMedCrossRefGoogle Scholar
  154. 154.
    Yang H, Roberts LJ, Shi MJ, Zhou LC, Ballard BR, Richardson A, Guo ZM (2004) Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E. Circ Res 95:1075–1081PubMedCrossRefGoogle Scholar
  155. 155.
    Yoshida K, Okamura T, Kimura H, Bredt DS, Snyder SH, Toda N (1993) Nitric oxide synthase-immunoreactive nerve fibers in dog cerebral and peripheral arteries. Brain Res 629:67–72PubMedCrossRefGoogle Scholar
  156. 156.
    Yoshida T, Maulik N, Engelman RM, Ho YS, Magnenat JL, Rousou JA, Flack JE 3rd, Deaton D, Das DK (1997) Glutathione peroxidase knockout mice are susceptible to myocardial ischemia reperfusion injury. Circulation 96(Flack JE):II-216–II-220Google Scholar
  157. 157.
    Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators. N Engl J Med 342:154–160PubMedCrossRefGoogle Scholar
  158. 158.
    Zalba G, San Jose G, Moreno MU, Fortuno MA, Fortuno A, Beaumont FJ, Diez J (2001) Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 38:1395–1399PubMedCrossRefGoogle Scholar
  159. 159.
    Zhang C, Hein TW, Wang W, Chang CI, Kuo L (2001) Constitutive expression of arginase in microvascular endothelial cells counteracts nitric oxide-mediated vasodilatory function. FASEB J 15:1264–1266PubMedCrossRefGoogle Scholar
  160. 160.
    Zhang C, Hein TW, Wang W, Miller MW, Fossum TW, McDonald MM, Humphrey JD, Kuo L (2004) Upregulation of vascular arginase in hypertension decreases nitric oxide-mediated dilation of coronary arterioles. Hypertension 44:935–943PubMedCrossRefGoogle Scholar
  161. 161.
    Zhang Y, Griendling KK, Dikalova A, Owens GK, Taylor WR (2005) Vascular hypertrophy in angiotensin II-induced hypertension is mediated by vascular smooth muscle cell-derived H2O2. Hypertension 46:732–737PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany

Personalised recommendations