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The Nox Family of NADPH Oxidases: Friend or Foe of the Vascular System?

  • Vascular Mechanisms (F Ruschitzka, Section Editor)
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Abstract

NADPH (nicotinamide adenine dinucleotide phosphate) oxidases are important sources of reactive oxygen species (ROS). In the vascular system, ROS can have both beneficial and detrimental effects. Under physiologic conditions, ROS are involved in signaling pathways that regulate vascular tone as well as cellular processes like proliferation, migration and differentiation. However, high doses of ROS, which are produced after induction or activation of NADPH oxidases in response to cardiovascular risk factors and inflammation, contribute to the development of endothelial dysfunction and vascular disease. In vascular cells, the NADPH oxidase isoforms Nox1, Nox2, Nox4, and Nox5 are expressed, which differ in their activity, response to stimuli, and the type of ROS released. This review focuses on the specific role of different NADPH oxidase isoforms in vascular physiology and their potential contributions to vascular diseases.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lambeth JD. Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med. 2007;43:332–47.

    Article  PubMed  CAS  Google Scholar 

  2. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87:245–313.

    Article  PubMed  CAS  Google Scholar 

  3. Lassegue B, Sorescu D, Szocs K, et al. Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res. 2001;88:888–94.

    Article  PubMed  CAS  Google Scholar 

  4. Sorescu GP, Song H, Tressel SL, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Circ Res. 2004;95:773–9.

    Article  PubMed  CAS  Google Scholar 

  5. Gorlach A, Brandes RP, Nguyen K, et al. 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.

    PubMed  CAS  Google Scholar 

  6. Chamseddine AH, Miller Jr FJ. Gp91phox contributes to NADPH oxidase activity in aortic fibroblasts but not smooth muscle cells. Am J Physiol Heart Circ Physiol. 2003;285:H2284–9.

    PubMed  CAS  Google Scholar 

  7. Ellmark SH, Dusting GJ, Fui MN, et al. The contribution of Nox4 to NADPH oxidase activity in mouse vascular smooth muscle. Cardiovasc Res. 2005;65:495–504.

    Article  PubMed  CAS  Google Scholar 

  8. Van Buul JD, Fernandez-Borja M, Anthony EC, et al. Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Antioxid Redox Signal. 2005;7:308–17.

    Article  PubMed  Google Scholar 

  9. Ago T, Kitazono T, Ooboshi H, et al. Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase. Circulation. 2004;109:227–33.

    Article  PubMed  CAS  Google Scholar 

  10. Belaiba RS, Djordjevic T, Petry A, et al. NOX5 variants are functionally active in endothelial cells. Free Radic Biol Med. 2007;42:446–59.

    Article  PubMed  CAS  Google Scholar 

  11. Jay DB, Papaharalambus CA, Seidel-Rogol B, et al. Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells. Free Radic Biol Med. 2008;45:329–35.

    Article  PubMed  CAS  Google Scholar 

  12. Cave A. Selective targeting of NADPH oxidase for cardiovascular protection. Curr Opin Pharmacol. 2009;9:208–13.

    Article  PubMed  CAS  Google Scholar 

  13. Hilenski LL, Clempus RE, Quinn MT, et al. Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004;24:677–83.

    Article  PubMed  CAS  Google Scholar 

  14. Hanna IR, Hilenski LL, Dikalova A, et al. Functional association of nox1 with p22phox in vascular smooth muscle cells. Free Radic Biol Med. 2004;37:1542–9.

    Article  PubMed  CAS  Google Scholar 

  15. Kuroda J, Nakagawa K, Yamasaki T, et al. The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells. Genes Cells. 2005;10:1139–51.

    Article  PubMed  CAS  Google Scholar 

  16. Helmcke I, Heumuller S, Tikkanen R, et al. Identification of structural elements in Nox1 and Nox4 controlling localization and activity. Antioxid Redox Signal. 2009;11:1279–87.

    Article  PubMed  CAS  Google Scholar 

  17. Clempus RE, Sorescu D, Dikalova AE, et al. Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol. 2007;27:42–8.

    Article  PubMed  CAS  Google Scholar 

  18. • Takac I, Schroder K, Zhang L, et al.: The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem 2011, 286:13304–13313. In this study, parts of the molecular basis of hydrogen peroxide formation by Nox4 are identified: Alterations in the E-loop switch the protein to superoxide formation.

    Article  PubMed  CAS  Google Scholar 

  19. Brandes RP, Schroder K. Differential vascular functions of Nox family NADPH oxidases. Curr Opin Lipidol. 2008;19:513–8.

    Article  PubMed  CAS  Google Scholar 

  20. • Hecker L, Vittal R, Jones T, et al.: NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 2009, 15:1077–1081. It is demonstrated that Nox4 is induced in pulmonary fibrosis and promotes disease progression by the stimulation of myofibroblast differentiation.

    Article  PubMed  CAS  Google Scholar 

  21. Manea A. NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology. Cell Tissue Res. 2010;342:325–39.

    Article  PubMed  CAS  Google Scholar 

  22. • Goettsch C, Goettsch W, Brux M, et al.: Arterial flow reduces oxidative stress via an antioxidant response element and Oct-1 binding site within the NADPH oxidase 4 promoter in endothelial cells. Basic Res Cardiol 2011, 106:551–561. This is one of the first studies to analyze the promoter of Nox4 and provide evidence for redox-dependent expression of the protein.

    Article  PubMed  CAS  Google Scholar 

  23. Duerrschmidt N, Stielow C, Muller G, et al. NO-mediated regulation of NAD(P)H oxidase by laminar shear stress in human endothelial cells. J Physiol. 2006;576:557–67.

    Article  PubMed  CAS  Google Scholar 

  24. • Lu X, Guo X, Wassall CD, et al.: Reactive oxygen species cause endothelial dysfunction in chronic flow overload. J Appl Physiol 2011, 110:520–527. High flow rates induce Nox2 and Nox4 in pigs, and antioxidative therapy blocks flow-induced remodeling, showing that redox-regulation in a large animal is involved in physiological remodeling processes.

    Article  PubMed  CAS  Google Scholar 

  25. • Schuhmacher S, Foretz M, Knorr M, et al.: α1AMP-activated protein kinase preserves endothelial function during chronic angiotensin II treatment by limiting Nox2 upregulation. Arterioscler Thromb Vasc Biol 2011, 31:560–566. A link between metabolic control and oxidative stress is provided by the demonstration that AMPK1α acts to limit Nox-dependent ROS formation in murine vessels.

    Article  PubMed  CAS  Google Scholar 

  26. Wang S, Zhang M, Liang B, et al. AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ Res. 2010;106:1117–28.

    Article  PubMed  CAS  Google Scholar 

  27. • Stanic B, Katsuyama M, Miller FJ Jr: An oxidized extracellular oxidation-reduction state increases Nox1 expression and proliferation in vascular smooth muscle cells via epidermal growth factor receptor activation. Arterioscler Thromb Vasc Biol 2010, 30:2234–2241. By a simple alteration in the extracellular concentration of cysteine to cystine, it is demonstrated that the redox milieu affects cellular signaling. The increase in the extracellular redox potential resulted in the induction of intracellular oxidizing enzymes.

    Article  PubMed  CAS  Google Scholar 

  28. Vasa-Nicotera M, Chen H, Tucci P, et al. miR-146a is modulated in human endothelial cell with aging. Atherosclerosis. 2011;217:326–30.

    Article  PubMed  CAS  Google Scholar 

  29. • Fu Y, Zhang Y, Wang Z, et al.: Regulation of NADPH oxidase activity is associated with miRNA-25-mediated NOX4 expression in experimental diabetic nephropathy. Am J Nephrol 2010, 32:581–589. The mechanism of diabetes-induced Nox4 expression is identified and related to a microRNA.

    Article  PubMed  CAS  Google Scholar 

  30. Kikuchi H, Kuribayashi F, Kiwaki N, et al. GCN5 regulates the superoxide-generating system in leukocytes via controlling gp91-phox gene expression. J Immunol. 2011;186:3015–22.

    Article  PubMed  CAS  Google Scholar 

  31. •• Schröder K, Kohnen A, Aicher A, et al.: NADPH oxidase Nox2 is required for hypoxia-induced mobilization of endothelial progenitor cells. Circ Res 2009, 105:537–544. It is identified that erythropoietin signaling in the bone marrow requires Nox2-dependent inactivation of the phosphatase SHP-2. This process is involved in vascular repair after carotid artery injury.

    Article  PubMed  Google Scholar 

  32. Sharma P, Chakraborty R, Wang L, et al. Redox regulation of interleukin-4 signaling. Immunity. 2008;29:551–64.

    Article  PubMed  CAS  Google Scholar 

  33. Liu RM, Choi J, Wu JH, et al. Oxidative modification of nuclear mitogen-activated protein kinase phosphatase 1 is involved in transforming growth factor beta1-induced expression of plasminogen activator inhibitor 1 in fibroblasts. J Biol Chem. 2010;285:16239–47.

    Article  PubMed  CAS  Google Scholar 

  34. Nakamura Y, Patrushev N, Inomata H, et al. Role of protein tyrosine phosphatase 1B in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells. Circ Res. 2008;102:1182–91.

    Article  PubMed  CAS  Google Scholar 

  35. Tabet F, Schiffrin EL, Callera GE, et al. 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. 2008;103:149–58.

    Article  PubMed  CAS  Google Scholar 

  36. Zimmerman MC, Takapoo M, Jagadeesha DK, et al. Activation of NADPH oxidase 1 increases intracellular calcium and migration of smooth muscle cells. Hypertension. 2011;58:446–53.

    Article  PubMed  CAS  Google Scholar 

  37. • Amberg GC, Earley S, Glapa SA: Local regulation of arterial L-type calcium channels by reactive oxygen species. Circ Res 2010, 107:1002–1010. This study identifies L-type calcium channels as an NADPH oxidase–modified redox target. It links Nox proteins to a direct, redox-dependent control of cerebral vascular tone.

    Article  PubMed  CAS  Google Scholar 

  38. Shimokawa H, Morikawa K. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Mol Cell Cardiol. 2005;39:725–32.

    Article  PubMed  CAS  Google Scholar 

  39. Larsen BT, Bubolz AH, Mendoza SA, et al. Bradykinin-induced dilation of human coronary arterioles requires NADPH oxidase-derived reactive oxygen species. Arterioscler Thromb Vasc Biol. 2009;29:739–45.

    Article  PubMed  CAS  Google Scholar 

  40. •• Ray R, Murdoch CE, Wang M, et al.: Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo. Arterioscler Thromb Vasc Biol 2011, 31:1368–1376. Endothelium-specific Nox4 transgenic mice are characterized. Remarkably, the increase in Nox4-dependent endothelial hydrogen peroxide formation improved vascular function and lowered the blood pressure.

    Article  PubMed  CAS  Google Scholar 

  41. Thomas SR, Chen K, Keaney Jr JF. Hydrogen peroxide activates endothelial nitric-oxide synthase through coordinated phosphorylation and dephosphorylation via a phosphoinositide 3-kinase-dependent signaling pathway. J Biol Chem. 2002;277:6017–24.

    Article  PubMed  CAS  Google Scholar 

  42. Burgoyne JR, Madhani M, Cuello F, et al. Cysteine redox sensor in PKGIa enables oxidant-induced activation. Science. 2007;317:1393–7.

    Article  PubMed  CAS  Google Scholar 

  43. Miller AA, Drummond GR, Schmidt HH, et al. NADPH oxidase activity and function are profoundly greater in cerebral versus systemic arteries. Circ Res. 2005;97:1055–62.

    Article  PubMed  CAS  Google Scholar 

  44. Ushio-Fukai M, Nakamura Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 2008;266:37–52.

    Article  PubMed  CAS  Google Scholar 

  45. Gorlach A, Diebold I, Schini-Kerth VB, et al. Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res. 2001;89:47–54.

    Article  PubMed  CAS  Google Scholar 

  46. Tojo T, Ushio-Fukai M, Yamaoka-Tojo M, et al. Role of gp91phox (Nox2)-containing NAD(P)H oxidase in angiogenesis in response to hindlimb ischemia. Circulation. 2005;111:2347–55.

    Article  PubMed  CAS  Google Scholar 

  47. Urao N, Inomata H, Razvi M, et al. Role of nox2-Based NADPH oxidase in bone marrow and progenitor cell function involved in neovascularization induced by hindlimb ischemia. Circ Res. 2008;103:212–20.

    Article  PubMed  CAS  Google Scholar 

  48. Schroder K, Schutz S, Schloffel I, et al. Hepatocyte growth factor induces a proangiogenic phenotype and mobilizes endothelial progenitor cells by activating nox2. Antioxid Redox Signal. 2011;15:915–23.

    Article  PubMed  Google Scholar 

  49. Al-Shabrawey M, Bartoli M, El-Remessy AB, et al. Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. Am J Pathol. 2005;167:599–607.

    Article  PubMed  CAS  Google Scholar 

  50. • Zhang M, Brewer AC, Schroder K, et al.: NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci U S A 2010, 107:18121–18126. Characterization of Nox4 transgenic and Nox4 knockout mice revealed that the enzyme controls hypoxia-driven VEGF expression. In the case of pressure overload, Nox4 facilitates cardiac angiogenesis and thereby prevents transition to heart failure.

    Article  PubMed  CAS  Google Scholar 

  51. Haddad P, Dussault S, Groleau J, et al. Nox2-derived reactive oxygen species contribute to hypercholesterolemia-induced inhibition of neovascularization: effects on endothelial progenitor cells and mature endothelial cells. Atherosclerosis. 2011;217:340–9.

    Article  PubMed  CAS  Google Scholar 

  52. Garrido-Urbani S, Jemelin S, Deffert C, et al. Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARalpha mediated mechanism. PLoS One. 2011;6:e14665.

    Article  PubMed  CAS  Google Scholar 

  53. Ebrahimian TG, Heymes C, You D, et al. NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes. Am J Pathol. 2006;169:719–28.

    Article  PubMed  CAS  Google Scholar 

  54. Schroder K, Helmcke I, Palfi K, et al. Nox1 mediates basic fibroblast growth factor-induced migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2007;27:1736–43.

    Article  PubMed  Google Scholar 

  55. • Craige SM, Chen K, Pei Y, et al.: NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation. Circulation 2011, 124:731–740. The angiogenic function of Nox4 endothelial–specific transgenic mice is characterized. Nox4 overexpression promotes angiogenesis in mice by increasing NO availability.

    Article  PubMed  CAS  Google Scholar 

  56. Forstermann U. Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal. Biol Chem. 2006;387:1521–33.

    Article  PubMed  Google Scholar 

  57. Loot AE, Schreiber JG, Fisslthaler B, et al. Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase. J Exp Med. 2009;206:2889–96.

    Article  PubMed  CAS  Google Scholar 

  58. • Chen CA, Wang TY, Varadharaj S, et al.: S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 2010, 468:1115–1118. Glutathionylation, a redox-dependent oxidative modification, is identified as a novel mechanism of eNOS uncoupling, demonstrating a novel mechanism of how oxidative stress leads to a breakdown of NO formation.

    Article  PubMed  CAS  Google Scholar 

  59. Matsuno K, Yamada H, Iwata K, et al. Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation. 2005;112:2677–85.

    Article  PubMed  CAS  Google Scholar 

  60. Gavazzi G, Banfi B, Deffert C, et al. Decreased blood pressure in NOX1-deficient mice. FEBS Lett. 2006;580:497–504.

    Article  PubMed  CAS  Google Scholar 

  61. Jung O, Schreiber JG, Geiger H, et al. gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension. Circulation. 2004;109:1795–801.

    Article  PubMed  CAS  Google Scholar 

  62. •• Violi F, Sanguigni V, Carnevale R, et al.: Hereditary deficiency of gp91(phox) is associated with enhanced arterial dilatation: results of a multicenter study. Circulation 2009, 120:1616–1622. This is the first report on the characterization of endothelium-dependent relaxation in patients with genetic loss of Nox2 activity. It is demonstrated that Nox2 also limits NO availability in humans.

    Article  PubMed  CAS  Google Scholar 

  63. • Pignatelli P, Carnevale R, Di Santo S, et al.: Inherited human gp91phox deficiency is associated with impaired isoprostane formation and platelet dysfunction. Arterioscler Thromb Vasc Biol 2011, 31:423–434. By the inclusion of patients with chronic granulomatous disease, it is demonstrated that Nox2 in humans controls redox processes in platelets as the formation of lipid peroxides.

    Article  PubMed  CAS  Google Scholar 

  64. •• Loukogeorgakis SP, van den Berg MJ, Sofat R, et al.: Role of NADPH oxidase in endothelial ischemia/reperfusion injury in humans. Circulation 2010, 121:2310–2316. With the inclusion of patients with mutations of the NADPH oxidase Nox2, it is demonstrated that the enzyme contributes to reperfusion-induced endothelial dysfunction after ischemia of the arm.

    Article  PubMed  CAS  Google Scholar 

  65. Hwang J, Saha A, Boo YC, et al. Oscillatory shear stress stimulates endothelial production of O2- from p47phox-dependent NAD(P)H oxidases, leading to monocyte adhesion. J Biol Chem. 2003;278:47291–8.

    Article  PubMed  CAS  Google Scholar 

  66. • Vecchione C, Carnevale D, Di Pardo A, et al.: Pressure-induced vascular oxidative stress is mediated through activation of integrin-linked kinase 1/betaPIX/Rac-1 pathway. Hypertension 2009, 54:1028–1034. The study provides direct evidence in mice that hypertension per se increases NADPH oxidase by stimulating the activity of Rac1.

    Article  PubMed  CAS  Google Scholar 

  67. Dikalova A, Clempus R, Lassegue B, et al. Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice. Circulation. 2005;112:2668–76.

    Article  PubMed  CAS  Google Scholar 

  68. Bendall JK, Rinze R, Adlam D, et al. Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice. Circ Res. 2007;100:1016–25.

    Article  PubMed  CAS  Google Scholar 

  69. Murdoch CE, om-Ruiz SP, Wang M, et al. Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction. Basic Res Cardiol. 2011;106:527–38.

    Article  PubMed  CAS  Google Scholar 

  70. Brandes RP, Takac I, Schroder K. No superoxide–no stress?: Nox4, the good NADPH oxidase! Arterioscler Thromb Vasc Biol. 2011;31:1255–7.

    Article  PubMed  CAS  Google Scholar 

  71. • Basuroy S, Tcheranova D, Bhattacharya S, et al.: Nox4 NADPH oxidase-derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-alpha-induced apoptosis. Am J Physiol Cell Physiol 2011, 300:C256–C265. CO is reported to be an effector of Nox4-dependent signaling. CO is also characterized as a molecule inhibiting Nox4 activity in endothelial cells.

    Article  PubMed  CAS  Google Scholar 

  72. Peterson JR, Sharma RV, Davisson RL. Reactive oxygen species in the neuropathogenesis of hypertension. Curr Hypertens Rep. 2006;8:232–41.

    Article  PubMed  CAS  Google Scholar 

  73. Capone C, Faraco G, Park L, et al. The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. Am J Physiol Heart Circ Physiol. 2011;300:H397–407.

    Article  PubMed  CAS  Google Scholar 

  74. Harrison DG, Guzik TJ, Goronzy J, et al. Is hypertension an immunologic disease? Curr Cardiol Rep. 2008;10:464–9.

    Article  PubMed  Google Scholar 

  75. Fujii A, Nakano D, Katsuragi M, et al. Role of gp91phox-containing NADPH oxidase in the deoxycorticosterone acetate-salt-induced hypertension. Eur J Pharmacol. 2006;552:131–4.

    Article  PubMed  CAS  Google Scholar 

  76. Zhang A, Jia Z, Wang N, et al. Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice. Kidney Int. 2011;80:51–60.

    Article  PubMed  CAS  Google Scholar 

  77. Zhang R, Harding P, Garvin JL, et al. Isoforms and functions of NAD(P)H oxidase at the macula densa. Hypertension. 2009;53:556–63.

    Article  PubMed  CAS  Google Scholar 

  78. Cabral PD, Garvin JL. Luminal flow regulates NO and O2(−) along the nephron. Am J Physiol Renal Physiol. 2011;300:F1047–53.

    Article  PubMed  CAS  Google Scholar 

  79. Carlstrom M, Lai EY, Ma Z, et al. Role of NOX2 in the regulation of afferent arteriole responsiveness. Am J Physiol Regul Integr Comp Physiol. 2009;296:R72–9.

    Article  PubMed  Google Scholar 

  80. • Niu XL, Madamanchi NR, Vendrov AE, et al.: Nox activator 1: a potential target for modulation of vascular reactive oxygen species in atherosclerotic arteries. Circulation 2010, 121:549–559. This study established a direct role of Noxa1, a cofactor of NADPH oxidases, in vascular pathology.

    Article  PubMed  CAS  Google Scholar 

  81. Guzik TJ, Chen W, Gongora MC, et al. Calcium-dependent NOX5 nicotinamide adenine dinucleotide phosphate oxidase contributes to vascular oxidative stress in human coronary artery disease. J Am Coll Cardiol. 2008;52:1803–9.

    Article  PubMed  CAS  Google Scholar 

  82. Judkins CP, Diep H, Broughton BR, et al. Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE−/− mice. Am J Physiol Heart Circ Physiol. 2010;298:H24–32.

    Article  PubMed  CAS  Google Scholar 

  83. Kirk EA, Dinauer MC, Rosen H, et al. Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2000;20:1529–35.

    Article  PubMed  CAS  Google Scholar 

  84. Hsich E, Segal BH, Pagano PJ, et al. Vascular effects following homozygous disruption of p47(phox): an essential component of NADPH oxidase. Circulation. 2000;101:1234–6.

    PubMed  CAS  Google Scholar 

  85. Sheehan AL, Carrell S, Johnson B, et al. Role for Nox1 NADPH oxidase in atherosclerosis. Atherosclerosis. 2011;216:321–6.

    Article  PubMed  CAS  Google Scholar 

  86. • Bae YS, Lee JH, Choi SH, et al.: Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: Toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circ Res 2009, 104:210–8, 21p. The tyrosine kinase Sky is established as a Nox2-dependent redox target in macrophages. This work associates lipoprotein with redox regulation in these cells.

  87. • Lee CF, Qiao M, Schroder K, et al.: Nox4 is a novel inducible source of reactive oxygen species in monocytes and macrophages and mediates oxidized low density lipoprotein-induced macrophage death. Circ Res 2010, 106:1489–1497. It is demonstrated that Nox4 is induced in macrophages in response to oxidized LDL (oxLDL) and mediates oxLDL-dependent signaling.

    Article  PubMed  CAS  Google Scholar 

  88. Pedruzzi E, Guichard C, Ollivier V, et al. NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol. 2004;24:10703–17.

    Article  PubMed  CAS  Google Scholar 

  89. Thomas M, Gavrila D, McCormick ML, et al. Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Circulation. 2006;114:404–13.

    Article  PubMed  CAS  Google Scholar 

  90. Gavazzi G, Deffert C, Trocme C, et al. NOX1 deficiency protects from aortic dissection in response to angiotensin II. Hypertension. 2007;50:189–96.

    Article  PubMed  CAS  Google Scholar 

  91. Lee MY, San MA, Mehta PK, et al. Mechanisms of vascular smooth muscle NADPH oxidase 1 (Nox1) contribution to injury-induced neointimal formation. Arterioscler Thromb Vasc Biol. 2009;29:480–7.

    Article  PubMed  CAS  Google Scholar 

  92. • Conrad M, Sandin A, Forster H, et al.: 12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases. Proc Natl Acad Sci U S A 2010, 107:15774–15779. It is demonstrated that by direct modification of cysteines, lipid peroxides are just as able as hydrogen peroxide to induce redox regulation by phosphatase inhibition.

    Article  PubMed  CAS  Google Scholar 

  93. Drummond GR, Selemidis S, Griendling KK, et al. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov. 2011;10:453–71.

    Article  PubMed  CAS  Google Scholar 

  94. • Sedeek M, Callera G, Montezano A, et al.: Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol Renal Physiol 2010, 299:F1348–F1358. A specific Nox inhibitor is used to prevent diabetes-induced renal fibrosis in mice.

    Article  PubMed  CAS  Google Scholar 

  95. Vendrov AE, Madamanchi NR, Niu XL, et al. NADPH oxidases regulate CD44 and hyaluronic acid expression in thrombin-treated vascular smooth muscle cells and in atherosclerosis. J Biol Chem. 2010;285:26545–57.

    Article  PubMed  CAS  Google Scholar 

  96. • Kuhns DB, Alvord WG, Heller T, et al.: Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 2010, 363:2600–2610. On the basis of a large cohort of patients with NADPH oxidase mutations, this study correlates ROS production of leukocytes with survival. It demonstrates that a slight inhibition of Nox activity does not increase mortality. A strong inverse correlation between ROS production and mortality is reported.

    Article  PubMed  CAS  Google Scholar 

  97. Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ J. 2010;74:818–26.

    Article  PubMed  CAS  Google Scholar 

  98. Antoniades C, Bakogiannis C, Tousoulis D, et al. Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity. Circulation. 2010;122:S66–73.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported by the Goethe-University and the German Research Foundation (SFB 815 & 834, Excellence Cluster Cardiopulmonary System—ECCPS).

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Correspondence to Ralf P. Brandes.

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Takac, I., Schröder, K. & Brandes, R.P. The Nox Family of NADPH Oxidases: Friend or Foe of the Vascular System?. Curr Hypertens Rep 14, 70–78 (2012). https://doi.org/10.1007/s11906-011-0238-3

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