Abstract
Reactive oxygen species (ROS) play a significant role in the pathogenesis of human vascular disorders associated with endothelial dysfunction, such as atherosclerosis, hypertension, coronary artery disease, and diabetic vascular disease. Moreover, recent data show that ROS are also relevant in venous diseases such as venous insufficiency or varicose vein disease (Guzik et al. 2011).
In general, the functional role of ROS in human vasculature is consistent with the majority of findings in animal models and cell culture, with main differences being related to the complexity of the system. This complexity is related not only to the concomitant expression of numerous oxidases (including Nox5) in human vessels in vivo but primarily to complicated regulation by many coinciding factors. While this is the case for every translational approach, for studies of reactive oxygen species, the task becomes particularly difficult. Furthermore, vascular pathologies in humans are much more dynamic and progress through more complex stages than observed in animal models. In humans, the sources and functional importance of ROS appear to differ at various stages of atherosclerotic plaque development. However, a number of solid studies have been performed on relatively large populations of subjects, and there is clear evidence as to the functional role of ROS in human vasculature and their regulation, which will be briefly discussed here.
Similar to animal models, ROS are generated by all layers of the vascular wall, the endothelium, vascular smooth muscle cells (VSMCs) in the media, fibroblasts, and incoming inflammatory cells in the adventitia (Berry et al. 2000). In these compartments, ROS may have divergent sources and roles, although its effects on endothelial function and vascular nitric oxide bioavailability appear to be particularly important in relation to human vascular disease.
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References
Adams V et al (2005) Impact of regular physical activity on the NAD(P)H oxidase and angiotensin receptor system in patients with coronary artery disease. Circulation 111(5):555–562
Alp NJ, Channon KM (2004) Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease. Arterioscler Thromb Vasc Biol 24(3):413–420
Anderson TJ et al (1995a) Close relation of endothelial function in the human coronary and peripheral circulations. JACC 26:1235–1241
Anderson TJ et al (1995b) The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 332(8):488–493
Antoniades C et al (2006) 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation 114(11):1193–1201
Antoniades C et al (2007) Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation. Circulation 116(24):2851–2859
Antoniades C et al (2008) GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. J Am Coll Cardiol 52(2):158–165
Antoniades C et al (2009) MTHFR 677 C > T Polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis. Circulation 119(18):2507–2515
Antoniades C et al (2011a) Induction of vascular GTP-cyclohydrolase I and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis. Circulation 124(17):1860–1870
Antoniades C et al (2011b) Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation 124(3):335–345
Azhar S (2010) Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. Future Cardiol 6(5):657–691
Azumi H et al (2002) Superoxide generation in directional coronary atherectomy specimens of patients with angina pectoris: important role of NAD(P)H oxidase. Arterioscler Thromb Vasc Biol 22(11):1838–1844
Baehner RL, Karnovsky ML (1968) Deficiency of reduced nicotinamide-adenine dinucleotide oxidase in chronic granulomatous disease. Science 162(3859):1277–1279
Bao W et al (2007) Effects of p38 MAPK Inhibitor on angiotensin II-dependent hypertension, organ damage, and superoxide anion production. J Cardiovasc Pharmacol 49(6):362–368
Bayraktutan U, Blayney L, Shah AM (2000) Molecular characterization and localization of the NAD(P)H oxidase components gp91-phox and p22-phox in endothelial cells. Arterioscler Thromb Vasc Biol 20(8):1903–1911
Berry C et al (2000) Investigation into the sources of superoxide in human blood vessels: angiotensin II increases superoxide production in human internal mammary arteries. Circulation 101(18):2206–2212
Betarbet R et al (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3(12):1301–1306
Bjelakovic G et al (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297(8):842–857
Bobryshev YV, Lord RS (1995) S-100 positive cells in human arterial intima and in atherosclerotic lesions. Cardiovasc Res 29(5):689–696
Bonetti PO, Lerman LO, Lerman A (2003) Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 23(2):168–175
Bowry VW et al (1995) Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein. J Biol Chem 270(11):5756–5763
Brownlee M (1995) Advanced protein glycosylation in diabetes and aging. Annu Rev Med 46:223–234
Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6):1615–1625
Bubolz AH et al (2012) Activation of endothelial TRPV4 channels mediates flow-induced dilation in human coronary arterioles: role of Ca2+ entry and mitochondrial ROS signaling. Am J Physiol Heart Circ Physiol 302(3):H634–H642
Cahilly C et al (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(4):391–395
Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87(10):840–844
Cai H et al (1999) NADH/NADPH oxidase p22 phox C242T polymorphism and coronary artery disease in the Australian population. Eur J Clin Invest 29(9):744–748
Cao X et al (2012) Angiotensin II-dependent hypertension requires cyclooxygenase 1-derived prostaglandin E2 and EP1 receptor signaling in the subfornical organ of the brain. Hypertension 59(4):869–876
Cascino T et al (2011) Adventitia-derived hydrogen peroxide impairs relaxation of the rat carotid artery via smooth muscle cell p38 mitogen-activated protein kinase. Antioxid Redox Signal 15(6):1507–1515
Cathcart MK (2004) Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis. Arterioscler Thromb Vasc Biol 24(1):23–28
Cosentino F et al (1997) High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 96(1):25–28
De Keulenaer GW et al (1998) Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase. Circ Res 82(10):1094–1101
Doehner W et al (2002) Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 105(22):2619–2624
Doughan AK, Harrison DG, Dikalov SI (2008) Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 102(4):488–496
Dowd P, Zheng ZB (1995) On the mechanism of the anticlotting action of vitamin E quinone. Proc Natl Acad Sci U S A 92(18):8171–8175
Drexler H et al (1992) Endothelial function in chronic congestive heart failure. Am J Cardiol 69(19):1596–1601
Ennezat PV et al (2011) Imagine how many lives you save: angiotensin-converting enzyme inhibition for atherosclerotic vascular disease in the present era of risk reduction. Expert Opin Pharmacother 12(6):883–897
Gardemann A et al (1999) The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals. Atherosclerosis 145(2):315–323
Gongora MC et al (2008) Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: a potential mechanism underlying adult respiratory distress syndrome. Am J Pathol 173(4):915–926
Greenberg ER (2005) Vitamin E supplements: good in theory, but is the theory good? Ann Intern Med 142(1):75–76
Gryglewski RJ, Palmer RM, Moncada S (1986) Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320(6061):454–456
Gutierrez AD et al (2009) The response of gamma vitamin E to varying dosages of alpha vitamin E plus vitamin C. Metabolism 58(4):469–478
Guzik TJ, Harrison DG (2006) Vascular NADPH oxidases as drug targets for novel antioxidant strategies. Drug Discov Today 11(11–12):524–533
Guzik TJ, Harrison DG (2007) Endothelial NF-kappaB as a mediator of kidney damage: the missing link between systemic vascular and renal disease? Circ Res 101(3):227–229
Guzik TJ et al (2000a) Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res 86(9):E85–E90
Guzik TJ et al (2000b) Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis. Circulation 102(15):1744–1747
Guzik TJ et al (2002) Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105(14):1656–1662
Guzik TJ et al (2004) Systemic regulation of vascular NAD(P)H oxidase activity and nox isoform expression in human arteries and veins. Arterioscler Thromb Vasc Biol 24(9):1614–1620
Guzik TJ et al (2006) Coronary artery superoxide production and nox isoform expression in human coronary artery disease. Arterioscler Thromb Vasc Biol 26(2):333–339
Guzik TJ et al (2008) Calcium-dependent NOX5 nicotinamide adenine dinucleotide phosphate oxidase contributes to vascular oxidative stress in human coronary artery disease. J Am Coll Cardiol 52(22):1803–1809
Guzik B et al (2011) Mechanisms of increased vascular superoxide production in human varicose veins. Pol Arch Med Wewn 121(9):279–286
Heitzer T et al (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104(22):2673–2678
Higgins P et al (2012) Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovasc Ther 30(4):217–226
Huang HY, Appel LJ (2003) Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr 133(10):3137–3140
Huraux C et al (1999) Superoxide production, risk factors, and endothelium-dependent relaxations in human internal mammary arteries. Circulation 99(1):53–59
Hwang J et al (2003) Pulsatile versus oscillatory shear stress regulates NADPH oxidase subunit expression. Implication for native LDL oxidation. Circ Res 93(12):1225–1232
Inoue N et al (1998) Polymorphism of the NADH/NADPH oxidase p22 phox gene in patients with coronary artery disease. Circulation 97(2):135–137
Jay DB et al (2008) Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells. Free Radic Biol Med 45(3):329–335
Kaminski PM, Wolin MS (1994) Hypoxia increases superoxide anion production from bovine coronary microvessels, but not cardiac myocytes, via increased xanthine oxidase. Microcirculation 1(4):231–236
Kim C, Kim JY, Kim JH (2008) Cytosolic phospholipase A(2), lipoxygenase metabolites, and reactive oxygen species. BMB Rep 41(8):555–559
Krzysciak W, Kozka M (2011) Generation of reactive oxygen species by a sufficient, insufficient and varicose vein wall. Acta Biochim Pol 58(1):89–94
Kubo SH et al (1991) Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 84(4):1589–1596
Kume N, Cybulsky MI, Gimbrone MA Jr (1992) Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest 90(3):1138–1144
Kuzkaya N et al (2003) Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem 278(25):22546–22554
Landmesser U et al (2002a) Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 106(24):3073–3078
Landmesser U et al (2002b) Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40(4):511–515
Landmesser U et al (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111(8):1201–1209
Lassegue B et al (2001) Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res 88(9):888–894
Laufs U et al (1998) Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97(12):1129–1135
Leyva F et al (1997) Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J 18(5):858–865
Loukogeorgakis SP et al (2010) Role of NADPH oxidase in endothelial ischemia/reperfusion injury in humans. Circulation 121(21):2310–2316
Lu X et al (2011) Reactive oxygen species cause endothelial dysfunction in chronic flow overload. J Appl Physiol 110(2):520–527
McLenachan JM et al (1990) Early evidence of endothelial vasodilator dysfunction at coronary branch points. Circulation 82(4):1169–1173
Miguel-Carrasco, J.L., et al., Captopril reduces cardiac inflammatory markers in spontaneously hypertensive rats by inactivation of NF-kB. J Inflamm (Lond), 2010. 7: p. 21.
Miller ER 3rd et al (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142(1):37–46
Morawietz H et al (2006a) Endothelial protection, AT1 blockade and cholesterol-dependent oxidative stress: the EPAS trial. Circulation 114(1 Suppl):I296–I301
Morawietz H et al (2006b) Increased cardiac endothelial nitric oxide synthase expression in patients taking angiotensin-converting enzyme inhibitor therapy. Eur J Clin Invest 36(10):705–712
Mueller CF et al (2005) ATVB in focus: redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol 25(2):274–278
Neunteufl T et al (1997) Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 129(1):111–118
Nielsen VG et al (1997) Xanthine oxidase mediates myocardial injury after hepatoenteric ischemia-reperfusion. Crit Care Med 25(6):1044–1050
Nissen SE et al (2004) Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 292(18):2217–2225
Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87(1):315–424
Paravicini TM et al (2012) Activation of vascular p38MAPK by mechanical stretch is independent of c-Src and NADPH oxidase: influence of hypertension and angiotensin II. J Am Soc Hypertens 6(3):169–178
Polikandriotis JA et al (2005) Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma-dependent mechanisms. Arterioscler Thromb Vasc Biol 25(9):1810–1816
Rajagopalan S et al (1996) Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 98(11):2572–2579
Ray R, Shah AM (2005) NADPH oxidase and endothelial cell function. Clin Sci (Lond) 109(3):217–226
Rey FE et al (2002) Perivascular superoxide anion contributes to impairment of endothelium-dependent relaxation: role of gp91(phox). Circulation 106(19):2497–2502
Rueckschloss U et al (2002) Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 22(11):1845–1851
Saavedra WF et al (2002) Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. Circ Res 90(3):297–304
Sauer, H., A.M. Shah, and F.R.M. Laurindo, Studies on cardiovascular disorders. Oxidative stress in applied basic research and clinical practice 2010, New York: Humana Press. xvii, 587 p.
Schramm A et al (2012) Targeting NADPH oxidases in vascular pharmacology. Vascul Pharmacol 56(5–6):216–231
Sherer TB et al (2007) Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson’s disease. J Neurochem 100(6):1469–1479
Shirodaria C et al (2007) Global improvement of vascular function and redox state with low-dose folic acid: implications for folate therapy in patients with coronary artery disease. Circulation 115(17):2262–2270
Sorescu D et al (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105(12):1429–1435
Sorrentino SA et al (2007) Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 116(2):163–173
Spiekermann S et al (2003) Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 107(10):1383–1389
Stanic B et al (2012) Increased epidermal growth factor-like ligands are associated with elevated vascular nicotinamide adenine dinucleotide phosphate oxidase in a primate model of atherosclerosis. Arterioscler Thromb Vasc Biol 32(10):2452–2460
Stephens NG et al (1996) Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 347(9004):781–786
Stirpe F, Della Corte E (1969) The regulation of rat liver xanthine oxidase. Conversion in vitro of the enzyme activity from dehydrogenase (type D) to oxidase (type O). J Biol Chem 244(14):3855–3863
Suh YA et al (1999) Cell transformation by the superoxide-generating oxidase Mox1. Nature 401(6748):79–82
Szocs K et al (2002) Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury. Arterioscler Thromb Vasc Biol 22(1):21–27
Tabet F et al (2008) Redox-sensitive signaling by angiotensin II involves oxidative inactivation and blunted phosphorylation of protein tyrosine phosphatase SHP-2 in vascular smooth muscle cells from SHR. Circ Res 103(2):149–158
Takimoto E, Kass DA (2007) Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 49(2):241–248
Tanner CM et al (2011) Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect 119(6):866–872
Touyz RM et al (2002) Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res 90(11):1205–1213
Ungvari Z et al (2003) Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol 23(3):418–424
Ushio-Fukai M et al (1999) Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem 274(32):22699–22704
Ushio-Fukai M et al (2001) Epidermal growth factor receptor transactivation by angiotensin II requires reactive oxygen species in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 21(4):489–495
Van Haaften RI et al (2001) Inhibition of human glutathione S-transferase P1-1 by tocopherols and alpha-tocopherol derivatives. Biochim Biophys Acta 1548(1):23–28
Vasquez-Vivar J, Kalyanaraman B, Martasek P (2003) The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications. Free Radic Res 37(2):121–127
Vecchione C et al (2005) Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma. J Exp Med 201(8):1217–1228
Violi F et al (2013) Reduced atherosclerotic burden in subjects with genetically determined low oxidative stress. Arterioscler Thromb Vasc Biol 33(2):406–412
Wagner AH et al (2000) Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 20(1):61–69
Wali MA et al (2002) Superoxide radical concentration and superoxide dismutase (SOD) enzyme activity in varicose veins. Ann Thorac Cardiovasc Surg 8(5):286–290
Wassmann S et al (2002) Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 22(2):300–305
West NEJ et al (2001) Enhanced superoxide production in experimental venous bypass graft intimal hyperplasia: role of NAD(P)H oxidase. Atheroscl Thromb Vasc Biol 21:189–194
Wilcox JN et al (1997) Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 17(11):2479–2488
Yamada Y et al (2002) Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med 347(24):1916–1923
Zafari AM et al (1998) Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension 32(3):488–495
Zernecke A, Shagdarsuren E, Weber C (2008) Chemokines in atherosclerosis: an update. Arterioscler Thromb Vasc Biol 28(11):1897–1908
Zima AV, Blatter LA (2006) Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res 71(2):310–321
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Guzik, T.J., Schramm, A., Czesnikiewicz-Guzik, M. (2014). Functional Implications of Reactive Oxygen Species (ROS) in Human Blood Vessels. In: Laher, I. (eds) Systems Biology of Free Radicals and Antioxidants. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30018-9_178
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