NAD(P)H Oxidase and Endothelial Dysfunction

G. Muller; H. Morawietz

doi:10.1055/s-0028-1086023

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2009; 41(2): 152-158
DOI: 10.1055/s-0028-1086023

Review

NAD(P)H Oxidase and Endothelial Dysfunction

G. Muller¹ , H. Morawietz¹

¹Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University of Technology Dresden, Dresden, Germany

Abstract

The regulation of endothelial function plays an important role in the development and progression of metabolic and cardiovascular diseases. A critical determinant of endothelial function is the balance between nitric oxide and reactive oxygen species. Endothelium-derived NO availability can be limited by enhanced formation of reactive oxygen species. Major sources of reactive oxygen species in the vessel wall are NAD(P)H oxidase complexes. This review summarizes the impact of vascular NAD(P)H oxidase-derived reactive oxygen species on atherosclerosis and endothelial dysfunction. Changes in NAD(P)H oxidase expression and activity have clinical implications. Mutations in NAD(P)H oxidase subunits can lead to impaired oxidative burst in leukocytes and chronic granulomatous disease. In contrast, normalization of increased expression and activity of NAD(P)H oxidase in endothelial dysfunction and vascular disorders can be considered as a novel therapeutic strategy in the treatment of cardiovascular diseases.

Key words

endothelial dysfunction - cardiovascular system - vessel wall - nitric oxide - oxidative stress - reactive oxygen species - NAD(P)H oxidase

Full Text

References

1 Panza JA, Quyyumi AA, Brush Jr JE, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990; 323 22-27
2 MacGorisk GM, Treasure CB. Endothelial dysfunction in coronary heart disease. Curr Opin Cardiol. 1996; 11 341-350
3 Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288 373-376
4 Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol. 2004; 15 1983-1992
5 Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986; 320 454-456
6 Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis?. Circulation. 2004; 109 II27-II33
7 Saely CH, Rein P, Drexel H. The metabolic syndrome and risk of cardiovascular disease and diabetes: experiences with the new diagnostic criteria from the International Diabetes Federation. Horm Metab Res. 2007; 39 642-650
8 Schutte AE, Olckers A. Metabolic syndrome risk in black South African women compared to Caucasian women. Horm Metab Res. 2007; 39 651-657
9 Franco OH, Karnik K, Bonneux L. The future of metabolic syndrome and cardiovascular disease prevention: polyhype or polyhope? Tales from the polyera. Horm Metab Res. 2007; 39 627-631
10 Rueckschloss U, Duerrschmidt N, Morawietz H. NADPH oxidase in endothelial cells: impact on atherosclerosis. Antioxid Redox Signal. 2003; 5 171-180
11 Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002; 82 47-95
12 Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). 2000; 79 170-200
13 Saini HK, Machackova J, Dhalla NS. Role of reactive oxygen species in ischemic preconditioning of subcellular organelles in the heart. Antioxid Redox Signal. 2004; 6 393-404
14 Keller M, Lidington D, Vogel L, Peter BF, Sohn HY, Pagano PJ, Pitson S, Spiegel S, Pohl U, Bolz SS. Sphingosine kinase functionally links elevated transmural pressure and increased reactive oxygen species formation in resistance arteries. FASEB J. 2006; 20 702-704
15 Colette C, Monnier L. Acute glucose fluctuations and chronic sustained hyperglycemia as risk factors for cardiovascular diseases in patients with type 2 diabetes. Horm Metab Res. 2007; 39 683-686
16 Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol. 2004; 24 816-823
17 Lambeth JD, Cheng G, Arnold RS, Edens WA. Novel homologs of gp91phox. Trends Biochem Sci. 2000; 25 459-461
18 Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004; 4 181-189
19 Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007; 87 245-313
20 Jones SA, O’Donnell VB, Wood JD, Broughton JP, Hughes EJ, Jones OT. Expression of phagocyte NADPH oxidase components in human endothelial cells. Am J Physiol. 1996; 271 H1626-H1634
21 Gorlach A, Brandes RP, Nguyen K, Amidi M, Dehghani F, Busse R. A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall. Circ Res. 2000; 87 26-32
22 Rueckschloss U, Galle J, Holtz J, Zerkowski HR, Morawietz H. 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. 2001; 104 1767-1772
23 Wallach TM, Segal AW. Analysis of glycosylation sites on gp91phox, the flavocytochrome of the NADPH oxidase, by site-directed mutagenesis and translation in vitro. Biochem J. 1997; 321 ((Pt 3)) 583-585
24 El-Benna J, PM-C D, Gougerot-Pocidalo M-A. Priming of the neutrophil NADPH oxidase activation: role of p47phox phosphorylation and NOX2 mobilization to the plasma membrane. Semin Immunopathol. 2008; 30 279-289
25 Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(–) and systolic blood pressure in mice. Circ Res. 2001; 89 408-414
26 Zhou MS, Hernandez Schulman I, Pagano PJ, Jaimes EA, Raij L. Reduced NAD(P)H oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood pressure. Hypertension. 2006; 47 81-86
27 Touyz RM, Yao G, Quinn MT, Pagano PJ, Schiffrin EL. p47phox associates with the cytoskeleton through cortactin in human vascular smooth muscle cells: role in NAD(P)H oxidase regulation by angiotensin II. Arterioscler Thromb Vasc Biol. 2005; 25 512-518
28 Forstermann U, Mugge A, Alheid U, Haverich A, Frolich JC. Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries. Circ Res. 1988; 62 185-190
29 Kelm M. The L-arginine-nitric oxide pathway in hypertension. Curr Hypertens Rep. 2003; 5 80-86
30 Zou M, Martin C, Ullrich V. Tyrosine nitration as a mechanism of selective inactivation of prostacyclin synthase by peroxynitrite. Biol Chem. 1997; 378 707-713
31 Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989; 83 1774-1777
32 Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM. 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
33 Radomski MW, Palmer RM, Moncada S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun. 1987; 148 1482-1489
34 Darley-Usmar VM, Hogg N, O’Leary VJ, Wilson MT, Moncada S. The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. Free Radic Res Commun. 1992; 17 9-20
35 Stielow C, Catar RA, Muller G, Wingler K, Scheurer P, Schmidt HH, Morawietz H. Novel Nox inhibitor of oxLDL-induced reactive oxygen species formation in human endothelial cells. Biochem Biophys Res Commun. 2006; 344 200-205
36 Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998; 97 1129-1135
37 Shaul PW. Regulation of endothelial nitric oxide synthase: location, location, location. Annu Rev Physiol. 2002; 64 749-774
38 Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G, Brovkovych V, Fellin R, Malinski T. Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production: key role of L-arginine availability. Circulation. 2000; 101 1261-1266
39 Chatterjee S, Ghosh N. Oxidized low density lipoprotein stimulates aortic smooth muscle cell proliferation. Glycobiology. 1996; 6 303-311
40 Lin SJ, Shyue SK, Shih MC, Chu TH, Chen YH, Ku HH, Chen JW, Tam KB, Chen YL. Superoxide dismutase and catalase inhibit oxidized low-density lipoprotein-induced human aortic smooth muscle cell proliferation: role of cell-cycle regulation, mitogen-activated protein kinases, and transcription factors. Atherosclerosis. 2007; 190 124-134
41 Cushing SD, Berliner JA, Valente AJ, Territo MC, Navab M, Parhami F, Gerrity R, Schwartz CJ, Fogelman AM. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA. 1990; 87 5134-5138
42 Kume N, Cybulsky MI, Gimbrone Jr MA. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest. 1992; 90 1138-1144
43 Yoshida H, Quehenberger O, Kondratenko N, Green S, Steinberg D. Minimally oxidized low-density lipoprotein increases expression of scavenger receptor A, CD36, and macrosialin in resident mouse peritoneal macrophages. Arterioscler Thromb Vasc Biol. 1998; 18 794-802
44 Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991; 88 1785-1792
45 Napoli C, Ackah E, Nigris F De, Del Soldato P, D’Armiento FP, Crimi E, Condorelli M, Sessa WC. Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice. Proc Natl Acad Sci USA. 2002; 99 12467-12470
46 Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. 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
47 Fukui T, Ishizaka N, Rajagopalan S, Laursen JB, Capers QT, Taylor WR, Harrison DG, Leon H de, Wilcox JN, Griendling KK. p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res. 1997; 80 45-51
48 Wang D, Chabrashvili T, Borrego L, Aslam S, Umans JG. Angiotensin II infusion alters vascular function in mouse resistance vessels: roles of O–·2 and endothelium. J Vasc Res. 2006; 43 109-119
49 Duerrschmidt N, Wippich N, Goettsch W, Broemme HJ, Morawietz H. Endothelin-1 induces NAD(P)H oxidase in human endothelial cells. Biochem Biophys Res Commun. 2000; 269 713-717
50 Rueckschloss U, Quinn MT, Holtz J, Morawietz H. 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. 2002; 22 1845-1851
51 Niemann B, Rohrbach S, Catar RA, Muller G, Barton M, Morawietz H. Native and oxidized low-density lipoproteins stimulate endothelin-converting enzyme-1 expression in human endothelial cells. Biochem Biophys Res Commun. 2005; 334 747-753
52 Muller G, Catar RA, Niemann B, Barton M, Knels L, Wendel M, Morawietz H. Upregulation of endothelin receptor B in human endothelial cells by low-density lipoproteins. Exp Biol Med (Maywood). 2006; 231 766-771
53 Catar RA, Muller G, Heidler J, Schmitz G, Bornstein SR, Morawietz H. Low-density lipoproteins induce the renin-angiotensin system and their receptors in human endothelial cells. Horm Metab Res. 2007; 39 801-805
54 Serin O, Konukoglu D, Firtina S, Mavis O. Serum oxidized low density lipoprotein, paraoxonase 1 and lipid peroxidation levels during oral glucose tolerance test. Horm Metab Res. 2007; 39 207-211
55 Rask-Madsen C, King GL. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab. 2007; 3 46-56
56 Rosen P, Osmers A. Oxidative stress in young zucker rats with impaired glucose tolerance is diminished by acarbose. Horm Metab Res. 2006; 38 575-586
57 Sethi AS, Lees DM, Douthwaite JA, Dawnay AB, Corder R. Homocysteine-induced endothelin-1 release is dependent on hyperglycaemia and reactive oxygen species production in bovine aortic endothelial cells. J Vasc Res. 2006; 43 175-183
58 Bellin C, Wiza DH de, Wiernsperger NF, Rosen P. Generation of reactive oxygen species by endothelial and smooth muscle cells: influence of hyperglycemia and metformin. Horm Metab Res. 2006; 38 732-739
59 Munzel T, Hink U, Heitzer T, Meinertz T. Role for NADPH/NADH oxidase in the modulation of vascular tone. Ann N Y Acad Sci. 1999; 874 386-400
60 Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M. Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol. 2000; 20 2175-2183
61 Heitzer T, Wenzel U, Hink U, Krollner D, Skatchkov M, Stahl RA, Macharzina R, Brasen JH, Meinertz T, Munzel T. 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
62 Cifuentes ME, Pagano PJ. Targeting reactive oxygen species in hypertension. Curr Opin Nephrol Hypertens. 2006; 15 179-186
63 Esper RJ, Nordaby RA, Vilarino JO, Paragano A, Cacharron JL, Machado RA. Endothelial dysfunction: a comprehensive appraisal. Cardiovasc Diabetol. 2006; 5 4
64 Al-Benna S, Hamilton CA, MacClure JD, Rogers PN, Berg GA, Ford I, Delles C, Dominiczak AF. Low-density lipoprotein cholesterol determines oxidative stress and endothelial dysfunction in saphenous veins from patients with coronary artery disease. Arterioscler Thromb Vasc Biol. 2006; 26 218-223
65 Krotz F, Engelbrecht B, Buerkle MA, Bassermann F, Bridell H, Gloe T, Duyster J, Pohl U, Sohn HY. The tyrosine phosphatase, SHP-1, is a negative regulator of endothelial superoxide formation. J Am Coll Cardiol. 2005; 45 1700-1706
66 Wei W, Chen ZW, Yang Q, Jin H, Furnary A, Yao XQ, Yim AP, He GW. Vasorelaxation induced by vascular endothelial growth factor in the human internal mammary artery and radial artery. Vascul Pharmacol. 2007; 46 253-259
67 He GW, Buxton BF, Rosenfeldt FL, Angus JA, Tatoulis J. Pharmacologic dilatation of the internal mammary artery during coronary bypass grafting. J Thorac Cardiovasc Surg. 1994; 107 1440-1444
68 Thakali KM, Lau Y, Fink GD, Galligan JJ, Chen AF, Watts SW. Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function. J Cardiovasc Pharmacol. 2006; 47 742-750
69 Guzik TJ, Sadowski J, Kapelak B, Jopek A, Rudzinski P, Pillai R, Korbut R, Channon KM. Systemic regulation of vascular NAD(P)H oxidase activity and nox isoform expression in human arteries and veins. Arterioscler Thromb Vasc Biol. 2004; 24 1614-1620
70 Pollock JD, Williams DA, Gifford MA, Li LL, Du X, Fisherman J, Orkin SH, Doerschuk CM, Dinauer MC. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet. 1995; 9 202-209
71 Jung O, Schreiber JG, Geiger H, Pedrazzini T, Busse R, Brandes RP. gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension. Circulation. 2004; 109 1795-1801
72 Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000; 86 494-501
73 Guzik TJ, West NE, Black E, MacDonald D, Ratnatunga C, Pillai R, Channon KM. Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res. 2000; 86 E85-E90
74 Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci. 2003; 24 471-478
75 Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation. 2002; 105 1429-1435
76 Kirk EA, Dinauer MC, Rosen H, Chait A, Heinecke JW, LeBoeuf RC. Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2000; 20 1529-1535
77 Hsich E, Segal BH, Pagano PJ, Rey FE, Paigen B, Deleonardis J, Hoyt RF, Holland SM, Finkel T. Vascular effects following homozygous disruption of p47(phox) : An essential component of NADPH oxidase. Circulation. 2000; 101 1234-1236
78 Barry-Lane PA, Patterson C, Merwe M van der, Hu Z, Holland SM, Yeh ET, Runge MS. p47phox is required for atherosclerotic lesion progression in ApoE(−/−) mice. J Clin Invest. 2001; 108 1513-1522
79 Vendrov AE, Hakim ZS, Madamanchi NR, Rojas M, Madamanchi C, Runge MS. Atherosclerosis is attenuated by limiting superoxide generation in both macrophages and vessel wall cells. Arterioscler Thromb Vasc Biol. 2007; 27 2714-2721
80 Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE, Loscalzo J, Cohen RA. Glucose-6-phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E(−/−) mice. Arterioscler Thromb Vasc Biol. 2006; 26 910-916
81 MacCormick ML, Gavrila D, Weintraub NL. Role of oxidative stress in the pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2007; 27 461-469
82 Zalba G, Fortuno A, Orbe J, San Jose G, Moreno MU, Belzunce M, Rodriguez JA, Beloqui O, Paramo JA, Diez J. Phagocytic NADPH oxidase-dependent superoxide production stimulates matrix metalloproteinase-9: implications for human atherosclerosis. Arterioscler Thromb Vasc Biol. 2007; 27 587-593
83 Berendes H, Bridges RA, Good RA. A fatal granulomatosus of childhood: the clinical study of a new syndrome. Minn Med. 1957; 40 309-312
84 Pao M, Wiggs EA, Anastacio MM, Hyun J, DeCarlo ES, Miller JT, Anderson VL, Malech HL, Gallin JI, Holland SM. Cognitive function in patients with chronic granulomatous disease: a preliminary report. Psychosomatics. 2004; 45 230-234
85 Quie PG, White JG, Holmes B, Good RA. In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J Clin Invest. 1967; 46 668-679
86 Baehner RL, Nathan DG. Leukocyte oxidase: defective activity in chronic granulomatous disease. Science. 1967; 155 835-836
87 Teahan C, Rowe P, Parker P, Totty N, Segal AW. The X-linked chronic granulomatous disease gene codes for the beta-chain of cytochrome b-245. Nature. 1987; 327 720-721
88 Malech HL, Hickstein DD. Genetics, biology and clinical management of myeloid cell primary immune deficiencies: chronic granulomatous disease and leukocyte adhesion deficiency. Curr Opin Hematol. 2007; 14 29-36
89 Violi F, Sanguigni V, Loffredo L, Carnevale R, Buchetti B, Finocchi A, Tesauro M, Rossi P, Pignatelli P. Nox2 is determinant for ischemia-induced oxidative stress and arterial vasodilatation: a pilot study in patients with hereditary Nox2 deficiency. Arterioscler Thromb Vasc Biol. 2006; 26 e131-e132
90 Carnevale R, Pignatelli P, Lenti L, Buchetti B, Sanguigni V, Santo S Di, Violi F. LDL are oxidatively modified by platelets via GP91(phox) and accumulate in human monocytes. FASEB J. 2007; 21 927-934
91 Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K, Zerkowski HR, Sawamura T, Holtz J. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation. 1999; 100 899-902
92 Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999; 100 2312-2318
93 Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley W, Teo K. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation. 2001; 103 919-925
94 Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008; 358 1547-1559
95 Ghiadoni L, Virdis A, Magagna A, Taddei S, Salvetti A. Effect of the angiotensin II type 1 receptor blocker candesartan on endothelial function in patients with essential hypertension. Hypertension. 2000; 35 501-506
96 Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation. 2000; 101 1653-1659
97 Morawietz H, Erbs S, Holtz J, Schubert A, Krekler M, Goettsch W, Kuss O, Adams V, Lenk K, Mohr FW, Schuler G, Hambrecht R. Endothelial protection, AT1 blockade and cholesterol-dependent oxidative stress: the EPAS trial. Circulation. 2006; 114 I296-I301
98 Dorenkamp M, Riad A, Stiehl S, Spillmann F, Westermann D, Du J, Pauschinger M, Noutsias M, Adams V, Schultheiss HP, Tschope C. Protection against oxidative stress in diabetic rats: role of angiotensin AT(1) receptor and beta 1-adrenoceptor antagonism. Eur J Pharmacol. 2005; 520 179-187
99 Riad A, Du J, Stiehl S, Westermann D, Mohr Z, Sobirey M, Doehner W, Adams V, Pauschinger M, Schultheiss HP, Tschope C. Low-dose treatment with atorvastatin leads to anti-oxidative and anti-inflammatory effects in diabetes mellitus. Eur J Pharmacol. 2007; 569 204-211
100 Adams V, Linke A, Krankel N, Erbs S, Gielen S, Mobius-Winkler S, Gummert JF, Mohr FW, Schuler G, Hambrecht R. Impact of regular physical activity on the NAD(P)H oxidase and angiotensin receptor system in patients with coronary artery disease. Circulation. 2005; 111 555-562
101 Jialal I, Devaraj S. Antioxidants and atherosclerosis: don't throw out the baby with the bath water. Circulation. 2003; 107 926-928
102 Riccioni G, Bucciarelli T, Mancini B, Ilio C Di, Capra V, D’Orazio N. The role of the antioxidant vitamin supplementation in the prevention of cardiovascular diseases. Expert Opin Investig Drugs. 2007; 16 25-32

Correspondence

H. MorawietzPhD

Division of Vascular Endothelium and Microcirculation

Department of Medicine III

Carl Gustav Carus Medical School

University of Technology Dresden

Fetscherstraße 74

01307 Dresden

Germany

Phone: +49/351/458 66 25

Fax: +49/351/458 63 54

Email: Henning.Morawietz@tu-dresden.de