Abstract
Vascular disease and vasomotor responses are largely influenced by oxidant stress. Superoxide is generated via the cellular oxidase systems, xanthine oxidase, and NADH/NADPH oxidases. Once formed, superoxides participate in a number of reactions, yielding various free radicals such as hydrogen peroxide, peroxynitrite, oxidized low-density lipoprotein, or hypochlorous acid. Numerous cellular antioxidant systems exist to defend against oxidant stress; glutathione and the enzymes superoxide dismutase and glutathione peroxidase are critical for maintaining the redox balance of the cell. However, the redox state is disrupted by certain vascular diseases. It appears that oxidant stress both promotes and is induced by diseases such as hypertension, atherosclerosis, and restenosis as well as by certain risk factors for coronary artery disease including hyperlipidemia, diabetes, and cigarette smoking. Once oxidant stress is invoked, characteristic pathophysiologic features ensue, namely adverse vessel reactivity, vascular smooth muscle cell proliferation, macrophage adhesion, platelet activation, and lipid peroxidation.
Similar content being viewed by others
References and Recommended Reading
Rajagopaian S, Kurz S, Munzel T, et al.: 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 1996, 97: 1916–1923.
Griendling KK, Wayne AR: Oxidative stress and cardiovascular disease. Circulation 1997, 96: 3264–3265.
Nunes GL, Robinson K, Kalynych A, et al.: Vitamins C and E inhibit 2 O2- production in the pig coronary artery. Circulation 1997, 96: 3593–3601.
Minor RL, Myer PR, Guerra R, et al.: Diet-induced atherosclerosis increases release of nitrogen oxides from rabbit aorta. J Clin Invest 1990, 86: 2109–2116.
Maxwell SR, Lip GYH: Free radicals and antioxidants in cardiovascular disease. Br J Clin Pharmacol 1997, 44: 307–317.
Rubin E, Farber JL: Cell Injury. In Pathology. Edited by Rubin E, Farber JL. Philadelphia: Lippincott-Raven; 1999: 1–35.
Fantone JC, Ward PA: Inflammation. In Pathology. Edited by Rubin E, Farber JL. Philadelphia: Lippincott-Raven; 1999: 36–75.
Darley-Usmar VM, McAndrew J, Patel R, et al.: Nitric oxide, free radicals, and cell signalling in cardiovascular disease. Biochem Soc Trans 1997, 25: 925–929.
Houston M, Estevez A, Chumley P, et al.: Binding of xanthine oxidase to vascular endothelium. J Biol Chem 1999, 274: 4985–4994.
Ohara Y, Peterson TE, Harrison DG: Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 1993, 91: 2546–2551.
Griendling KK, Minieri CA, Ollerenshaw JD, et al.: Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994, 74: 1141–1148.
DeLeo FR, Ulman KV, Davis AR, et al.: Assembly of the Human Neutrophil NADPH oxidase involves binding of p67phox and flavocytochrome b to a common functional domain in p47phox. J Biol Chem 1996, 271: 17013–17020.
Vasquez-Vivar J, Martasek P, Hogg N, et al.: Electron spin resonance spin trapping detection of superoxide generated by neuronal nitric oxide synthase. Meth Enzymol 1999, 301: 169–177.
Pou S, Keaton L, Surichamorn W, et al.: Mechanism of superoxide generation by neuronal nitric oxide synthase. J Biol Chem 1999, 274: 9573–9580.
Fridovich I.: Superoxide anion radical (O2-), superoxide dismutases, and related matters. J Biol Chem 1997, 272: 18515–18517.
Girotti AW: Lipid hydroperoxide generation, turnover, and effector action in biological systems. J Lipid Res 1998, 39: 1529–1542.
Koppenol WH: The basic chemistry of nitrogen monoxide and peroxynitrite. Free Rad Biol Med 1998, 25: 385–391.
Squadrito GL, Pryor WA: Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Rad Biol Med 1998, 25: 392–403.
Wink DA, Mitchell JB: Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Rad Biol Med 1998, 25: 434–456.
Briviba K, Sies H: Nonenzymatic antioxidant defense systems. In Natural Antioxidants in Human Health and Disease. Edited by Frei B. San Diego: Academic Press; 1994: 107–128.
Meister A: Glutathione-ascorbic acid antioxidant system in animals. J Biol Chem 1994, 269: 9397–9400.
Anderson ME: Glutathione and glutathione delivery compounds. In Antioxidants in Disease Mechanisms and Therapy, Advances in Pharmacology. Edited by Sies H. San Diego: Academic Press; 1997: 65–78.
Suzuki YJ, Forman HJ, Sevanian A.: Oxidants as stimulators of signal transduction. Free Rad Biol Med 1997, 22: 269–285.
Liao JK: Endothelium and acute coronary syndromes. Clin Chem 1998, 44: 1799–1808.
Gibbons GH, Dzau VJ: Molecular therapies for vascular diseases. Science 1996, 272: 689–693.
Bruckdorfer KR: Lipid oxidation products and vascular function. Free Rad Res 1998, 28: 573–581.
Tanner FC, Noll G, Boulanger CM, et al.: Oxidized low-density lipoproteins inhibit relaxations of porcine coronary arteries: role of scavenger receptor and endothelium-derived nitric oxide. Circulation 1991, 83: 2012–2020.
Munzel T, Sayegh H, Freeman BA, et al.: Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 1995, 95: 187–194.
Ambrosio G, Tritto I, Golino P: Reactive oxygen metabolites and arterial thrombosis. Cardiovasc Res 1997, 34: 445–452.
Huang PL, Huang Z, Mashimo H, et al.: Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995, 377: 239–242.
Moroi M, Zhang L, Yasuda T, et al.: Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest 1998, 101: 1225–1232.
Silacci P, Hayoz D: Oxidative stress as the triggering event for vascular remodeling. Nephrol Dial Transplant 1998, 13: 1343–1346.
Palmer RMJ, Ferrige AG, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987, 327: 524–526.
Harrison DG: Endothelial function and oxidant stress. Clin Cardiol 1997, 20(SII): II-11–II-17.
Marui N, Offermann MK, Swerlick R, et al.: Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 1993, 92: 1866–1874.
Collins T, Read MA, Neish AS, et al.: Transcriptional regulation of endothelial cell adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J 1995, 9: 899–909.
De Caterina R, Libby P, Peng HB, et al.: Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectivity reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995, 96: 60–68.
Khan BV, Harrison DG, Olbrych MT, et al.: Nitric oxide regulates vascular cell adhesion molecule-1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 1996, 93: 9114–9119.
Spiecker M, Peng HB, Liao JK: Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IκBα. J Biol Chem 1997, 272: 30961–30974.
Peng HB, Libby P, Liao JK: Induction and stabilization of IκBα by nitric oxide mediated inhibition of NF-kBa. J Biol Chem 1995, 270: 14214–14219.
Pieper GM, Moore-Hilton G, Roza A: Evaluation of the mechanism of endothelial dysfunction in the genetically diabetic BB rat. Life Sci 1996, 58: 147–152.
Freedman JE, Loscalzo J, Benoit SE, et al.: Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis. J Clin Invest 1996, 97: 979–987.
Welch GN, Upchurch GR, Loscalzo J: Homocysteine, oxidative stress, and vascular disease. Hosp Pract 1997, 32: 81–92.
Chin JH, Azhar S, Hoffman BB: Inactivation of endothelium-derived relaxing factor by oxidized lipoproteins. J Clin Invest 1992, 89: 10–18.
Loscalzo J: The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 1996, 98: 5.
Upchurch GR Jr., Welch GN, Fabian AJ, et al.: Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997, 272: 17012–17017.
Howard AB, Alexander RW, Nerem RM, et al.: Cyclic strain induces an oxidative stress in endothelial cells. Am J Physiol (Heart Circ Physiol) 1997, 272: C421–427.
Uematsu M, Ohara Y, Navas JP, et al.: Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am J Physiol (Cell Physiol) 1995, 269: C1371–1378.
Nishida K, Harrison DG, Navas JP, et al.: Molecular cloning and characterization of the constituitive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest 1992, 90: 2092–2096.
Inove N, Ramasamy S, Fukai T, et al.: Shear stress modulates expression of Cu/Zn superoxide dismutase in human aortic endothelial cells. Circ Res 1996, 79: 32–37.
Griendling KK, Ushio-Fukai M: Redox control of vascular smooth muscle proliferation. J Lab Clin Med 1998, 132: 9–15.
Boscoboinik D, Szewceyk A, Hensey C, et al.: Inhibition of cell proliferation by a-tocopherol. Role of protein kinase C. J Biol Chem 1991, 266: 6188–6194.
Tsai JC, Jain M, Hsieh C-M, et al.: Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells. J Biol Chem 1996, 271: 3667–3670.
Gong KW, Zhu GY, Wang LH, et al.: Effect of active oxygen species on intimal proliferation in rat aorta after arterial injury. J Vasc Res 1996, 33: 42–46.
Lafont AM, Chai YC, Cornhill JF, et al.: Effect of alpha-tocopherol on restenosis after angioplasty in a model of experimental atherosclerosis. J Clin Invest 1995, 95: 1018–1025.
Konneh MK, Rutherford C, Li SR, et al.: Vitamin E inhibits the intimal response to balloon catheter injury in the carotid artery of the cholesterol-fed rat. Atherosclerosis 1995, 113: 29–39.
Schnackenberg CG, Welch WJ, Wilcox CS: Normalization of blood pressure and renal vascular resistance in SHR with a membrance-permeable superoxide dismutase mimetic: role of nitric oxide. Hypertension 1998, 32: 59–64.
Kerr S, Brosnan MJ, McIntyre M, et al.: Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium. Hypertension 1999, 33: 1353–1358.
Di Wang H, Hope S, Du Y, et al.: Paracrine role of adventitial superoxide anion in mediating spontaneous tone of the isolated rat aorta in angiotensin II-induced hypertension. Hypertension 1999, 33: 1225–1232.
Heitzer T, Wenzel U, Wenzel U, et al.: Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase. C. Kidney Int 1999, 55: 252–260.
Newez MA, Nawal NN: Effect of alpha-tocopherol on lipid peroxidation and total antioxidant status in spontaneously hypertensive rats. Am J Hypertens 1998, 12: 1480–1485.
Russo C, Olivieri O, Girelli D, et al.: Anti-oxidant status and lipid peroxidation in patients with essential hypertension. J Hypertens 1998, 16: 1267–1271.
Senna SM, Moraes RB, Bravo MF, et al.: Effects of prostaglandins and nitric oxide on rat macrophage lipid metabolism in culture: implications for arterial wall-leukocyte interplay in atherosclerosis. Biochem Mol Biol International 1998, 46: 1007–1018.
Chatterjee S: Sphingolipids in atherosclerosis and vascular biology. Arterioscler Thromb Vasc Biol 1998, 18: 1523–1533.
Luoma JS, Stralin P, Marklund SL, et al.: Expression of extracellular SOD and iNOS in macrophages and smooth muscle cells in human and rabbit atherosclerotic lesions: colocalization with epitopes characteristic of oxidized LDL and peroxynitrite-modified proteins. Arterioscler Thromb Vasc Biol 1998, 8: 157–167.
Fukai T, Galis ZS, Meng XP, et al.: Vascular expression of extracellular superoxide dismutase in atherosclerosis. J Clin Invest 1998, 101: 2101–2111.
Rosenblat M, Aviram M: Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies. Free Rad Biol Med 1998, 24: 305–317.
Inoue N, Ohara Y, Fukai T, et al.: Probucol improves endothelial-dependent relaxation and decreases vascular superoxide production in cholesterol-fed rabbits. Am J Med Sci 1998, 315: 242–247.
Kurose I, Wolf RE, Grisham MB, et al.: Hypercholesterolemia enhances oxidant production in mesenteric venules exposed to Ischemia/Reperfusion. Arterioscler Thromb Vasc Biol 1998, 18: 1583–1588.
Boger RH, Bode-Boger SM, Phivthong-ngam L, et al.: Dietary L-arginine and alpha-tocopherol reduce vascular oxidative stress and preserve endothelial function in hypercholesterolemic rabbits via different mechanisms. Atherosclerosis 1998, 141: 31–43.
Verhaar MC, Wever RM, Kastelein JJ, et al.: 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 1998, 97: 237–241.
Simon E, Paul JL, Atger V, et al.: Erythrocyte antioxidant status in asymptomatic hypercholesterolemic men. Atherosclerosis 1998, 138: 375–381.
Berliner JA, Territo M, Andalibi A, et al.: Modified lipoproteins and atherosclerosis. In Cellular and Molecular Biology of Atherosclerosis. Edited by Gotto AM. London: Springer-Uerlag; 1992: 77–81.
Graier WR, Posch K, Wascher TC, et al.: Role of superoxide anions in changes of endothelial vasoactive response during acute hyperglycemia. Horm Metabol Res 1997, 29: 622–626.
Ruiz C, Alegria A, Barbera R, et al.: Lipid peroxidation and antioxidant enzyme activities in patients with type 1 diabetes mellitus. Scand J Clin Invest 1999, 59: 99–105.
Schleicher ED, Wagner E, Nerlich AG: Increased accumulation of the glycoxidation product N-ε-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 1997, 99: 457–468.
Kajanachumpol S, Komindr S, Mahaisiriyodom A: Plasma lipid peroxide and antioxidant levels in diabetic patients. J Med Assoc Thailand 1997, 80: 372–377.
Jain SK, Kannan K, Lim G: Ketosis (acetoacetate) can generate oxygen radicals and cause increased lipid peroxidation and growth inhibition in human endothelial cells. Free Rad Biol Med 1998, 25: 1083–1088.
Davi G, Ciabottoni G, Consol A, et al.: In vivo formation of 8-iso-prostaglandin F2α and platelet activation in diabetes mellitus: effects of impaired metabolic control. Circulation 1999; 99: 224–229.
Yerneni KK, Bai W, Khan BV, et al.: Hyperglycemia-induced activation of nuclear transcription factor κB in vascular smooth muscle cells. Diabetes 1999, 48: 855–864.
Su Y, Han W, Giraldo C, et al.: Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. Am J Respir Cell Mol Biol 1998, 119: 819–825.
Gilks CB, Price K, Wright JL, et al.: Antioxidant gene expression in rat lung after exposure to cigarette smoke. Am J Pathol 1998, 152: 269–278.
Sugiyama S, Kugiyama K, Ohgushi M, et al.: Supersensitivity of atherosclerotic artery to constrictor effect of cigarette smoke extract. Cardiovas Res 1998, 38: 508–515.
Keaney JF Jr., Xu A, Cunningham D, et al.: Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. J Clin Invest 1995, 95: 2520–2529.
Keaney JF Jr., Gaziano JM, Xu A, et al.: Low-dose alpha-tocopherol improves and high-dose alpha-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits. J Clin Invest 1994, 93: 844–851.
Cunningham DG, Vita JA, Keaney JF Jr.: Alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL. Clin Res 1994, 42:175A.
Diaz MN, Frei B, Vita JA, et al.: Mechanisms of disease: antioxidants and atherosclerotic heart disease. N Engl J Med 1997, 337: 408–416.
Rimm EB, Stampfer MJ, Ascherio A, et al.: Vitamin E consumption and the risk of coronary disease in men. N Engl J Med 1993, 328: 1450–1456.
Stampfer MJ, Hennekens CH, Manson JE, et al.: Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993, 328: 1444–1449.
Wallidus G, Erikson U, Olsson AG, et al.: The effect of probucol on femoral atherosclerosis: the Probucol Quantitative Regression Swedish Trial (PQRST). Am J Cardiol 1994, 74: 875–883.
The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994, 330: 1029–1035.
Stephens NG, Parsons A, Schofield PM, et al.: Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996, 347: 781–786.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Maytin, M., Leopold, J. & Loscalzo, J. Oxidant stress in the vasculature. Curr Atheroscler Rep 1, 156–164 (1999). https://doi.org/10.1007/s11883-999-0012-z
Issue Date:
DOI: https://doi.org/10.1007/s11883-999-0012-z