NOX enzymes as novel targets for drug development

Springer Science and Business Media LLC - Tập 30 - Trang 339-363 - 2008
J. David Lambeth1, Karl-Heinz Krause2, Robert A. Clark3
1Emory University, Atlanta, USA
2University of Geneva, Geneva, Switzerland
3University of Texas Health Science Center, San Antonio, USA

Tóm tắt

The members of the NOX/DUOX family of NADPH oxidases mediate such physiologic functions as host defense, cell signaling, and thyroid hormone biosynthesis through the generation of reactive oxygen species (ROS), including superoxide anion and hydrogen peroxide. Moreover, ROS are involved in a broad range of fundamental biochemical and cellular processes, and data accumulated in recent years indicate that the NOX enzymes comprise one of the most important biological sources of ROS. Given the high biochemical reactivity of ROS, it is not surprising that they have been implicated in a wide variety of pathologies and diseases. Prominent among the settings that feature ROS-mediated tissue injury are disorders associated with inflammation, aging, and progressive degenerative changes in cells and organ systems, and it appears that essentially no organ system is exempt. Among the disorders currently believed to be mediated at least in part by NOX-derived ROS are hypertension, aortic aneurysm, myocardial infarction (and other ischemia–reperfusion disorders), pulmonary fibrosis and hypertension, amyotropic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, ischemic stroke, diabetic nephropathy, and renal cell carcinoma. Several small-molecule and peptide inhibitors of the NOX enzymes have been useful in experimental studies, but issues of specificity, potency, and toxicity militate against any of the existing published compounds as candidates for drug development. Given the broad array of disease targets documented in recent work, the time is here for vigorous efforts to develop clinically useful inhibitors of the NOX enzymes. As most (though not all) NOX-related diseases appear to be mediated by a single member of the NOX family, agents with isoform specificity will be preferred, although broadly active NOX inhibitors may prove to be useful in some settings.

Tài liệu tham khảo

Abdala-Valencia H, Earwood J, Bansal S, Jansen M, Babcock G, Garvy B, Wills-Karp M, Cook-Mills JM (2007) Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma. Am J Physiol Lung Cell Mol Physiol 292:L1111–L1125 Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27:1129–1138 Agarwal A, Saleh RA, Bedaiwy MA (2003) Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril 79:829–843 Aitken RJ, Baker MA (2004) Oxidative stress and male reproductive biology. Reprod Fertil Dev 16:581–588 Akasaki T, Ohya Y, Kuroda J, Eto K, Abe I, Sumimoto H, Iida M (2006) Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system. Hypertens Res 29:813–820 Al-Mehdi AB, Zhao G, Dodia C, Tozawa K, Costa K, Muzykantov V, Ross C, Blecha F, Dinauer M, Fisher AB (1998) Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+. Circ Res 83:730–737 Al-Shabrawey M, Bartoli M, El-Remessy AB, Platt DH, Matragoon S, Behzadian MA, Caldwell RW, Caldwell RB (2005) Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. Am J Pathol 167:599–607 Anantharam V, Kaul S, Song C, Kanthasamy A, Kanthasamy AG (2007) Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells. Neurotoxicology 28:988–997 Arbiser JL, Petros JA, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD (2002) Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci 99:715–720 Arnold RS, He J, Remo A, Ritsick D, Yin-Goen Q, Lambeth JD, Datta MW, Young AN, Petros JA (2007) Nox1 expression determines cellular reactive oxygen and modulates c-fos-induced growth factor, interleukin-8, and Cav-1. Am J Pathol 171:2021–2032 Asaba K, Tojo A, Onozato ML, Goto A, Quinn MT, Fujita T, Wilcox CS (2005) Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int 67:1890–1898 Babior BM, Lambeth JD, Nauseef W (2002) The neutrophil NADPH oxidase. Arch Biochem Biophys 397:342–344 Banfi B, Malgrange B, Knisz J, Steger K, Dubois-Dauphin M, Krause KH (2004) NOX3: a superoxide-generating NADPH oxidase of the inner ear. J Biol Chem 279:46065–46072 Banfi B, Molnar G, Maturana A, Steger K, Hegedus B, Demaurex N, Krause KH (2001) A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes. J Biol Chem 276:37594–37601 Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, Fraticelli P, Sambo P, Funaro A, Kazlauskas A, Avvedimento EV, Gabrielli A (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354:2667–2676 Barrett WC, DeGnore JP, Keng YF, Zhang ZY, Yim MB, Chock PB (1999) Roles of superoxide radical anion in signal transduction mediated by reversible regulation of protein-tyrosine phosphatase 1B. J Biol Chem 274:34543–34546 Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313 Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan LL (2007) Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318:1645–1647 BelAiba RS, Djordjevic T, Petry A, Diemer K, Bonello S, Banfi B, Hess J, Pogrebniak A, Bickel C, Gorlach A (2007) NOX5 variants are functionally active in endothelial cells. Free Radic Biol Med 42:446–459 Ben-Shaul V, Lomnitski L, Nyska A, Zurovsky Y, Bergman M, Grossman S (2001) The effect of natural antioxidants, NAO and apocynin, on oxidative stress in the rat heart following LPS challenge. Toxicol Lett 123:1–10 Bendall JK, Cave AC, Heymes C, Gall N, Shah AM (2002) Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 105:293–296 Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117:568–575 Beswick RA, Dorrance AM, Leite R, Webb RC (2001) NADH/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat. Hypertension 38:1107–1111 Blanchard TG, Yu F, Hsieh CL, Redline RW (2003) Severe inflammation and reduced bacteria load in murine helicobacter infection caused by lack of phagocyte oxidase activity. J Infect Dis 187:1609–1615 Block K, Gorin Y, Hoover P, Williams P, Chelmicki T, Clark RA, Yoneda T, Abboud HE (2007) NAD(P)H oxidases regulate HIF-2alpha protein expression. J Biol Chem 282:8019–8026 Bloxham DP (1979) The relationship of diphenyleneiodonium-induced hypoglycaemia to the specific covalent modification of NADH-ubiquinone oxidoreductase. Biochem Soc Trans 7:103–106 Boldogh I, Bacsi A, Choudhury BK, Dharajiya N, Alam R, Hazra TK, Mitra S, Goldblum RM, Sur S (2005) ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation. J Clin Invest 115:2169–2179 Boota A, Johnson B, Lee KL, Blaskovich MA, Liu SX, Kagan VE, Hamilton A, Pitt B, Sebti SM, Davies P (2000) Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle. Am J Physiol Lung Cell Mol Physiol 278:L329–L334 Brar SS, Kennedy TP, Sturrock AB, Huecksteadt TP, Quinn MT, Murphy TM, Chitano P, Hoidal JR (2002) NADPH oxidase promotes NF-kappaB activation and proliferation in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 282:L782–L795 Brodsky SV, Zhang F, Nasjletti A, Goligorsky MS (2004) Endothelium-derived microparticles impair endothelial function in vitro. Am J Physiol Heart Circ Physiol 286:H1910–H1915 Brookes PS, Levonen AL, Shiva S, Sarti P, Darley-Usmar VM (2002) Mitochondria: regulators of signal transduction by reactive oxygen and nitrogen species. Free Radic Biol Med 33:755–764 Burdon R (1995) Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 18:775–794 Byrne JA, Grieve DJ, Bendall JK, Li JM, Gove C, Lambeth JD, Cave AC, Shah AM (2003) Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy. Circ Res 93:802–805 Carmiel-Haggai M, Cederbaum AI, Nieto N (2005) A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. FASEB J 19:136–138 Castello PR, Drechsel DA, Patel M (2007) Mitochondria are a major source of paraquat-induced reactive oxygen species production in the brain. J Biol Chem 282:14186–14193 Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM (2006) NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 8:691–728 Cayatte AJ, Rupin A, Oliver-Krasinski J, Maitland K, Sansilvestri-Morel P, Boussard MF, Wierzbicki M, Verbeuren TJ, Cohen RA (2001) S17834, a new inhibitor of cell adhesion and atherosclerosis that targets nadph oxidase. Arterioscler Thromb Vasc Biol 21:1577–84 Cejkova J, Labsky J, Vacik J (1998) Reactive oxygen species (ROS) generated by xanthine oxidase in the corneal epithelium and their potential participation in the damage of the corneal epithelium after prolonged use of contact lenses in rabbits. Acta Histochem 100:171–184 Chamulitrat W, Huber A, Riedel HD, Stremmel W (2007) Nox1 induces differentiation resistance in immortalized human keratinocytes generating cells that express simple epithelial keratins. J Invest Dermatol 127:2171–2183 Chamulitrat W, Stremmel W, Kawahara T, Rokutan K, Fujii H, Wingler K, Schmidt HH, Schmidt R (2004) A constitutive NADPH oxidase-like system containing gp91phox homologs in human keratinocytes. J Invest Dermatol 122:1000–1009 Chen P, Guo AM, Edwards PA, Trick G, Scicli AG (2007) Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis. Am J Physiol Regul Integr Comp Physiol 293:R1619–R1629 Choi JA, Kim EY, Song H, Kim C, Kim JH (2008) Reactive oxygen species are generated through a BLT2-linked cascade in Ras-transformed cells. Free Radic Biol Med 44:624–634 Choi KM, Kang CM, Cho ES, Kang SM, Lee SB, Um HD (2007) Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK. Oncol Rep 17:1183–1188 Chu KY, Leung PS (2007) Angiotensin II Type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet beta-cell function in young Type 2 diabetic mice. Antioxid Redox Signal 9:869–878 Cifuentes ME, Pagano PJ (2006) Targeting reactive oxygen species in hypertension. Curr Opin Nephrol Hypertens 15:179–186 Colmenero J, Bataller R, Sancho-Bru P, Bellot P, Miquel R, Moreno M, Jares P, Bosch J, Arroyo V, Caballeria J, Gines P (2007) Hepatic expression of candidate genes in patients with alcoholic hepatitis: correlation with disease severity. Gastroenterology 132:687–697 Cross AR (1987) The inhibitory effects of some iodonium compounds on the superoxide generating system of neutrophils and their failure to inhibit diaphorase activity. Biochem Pharmacol 36:489–493 Cross AR, Jones OT (1986) The effect of the inhibitor diphenylene iodonium on the superoxide-generating system of neutrophils. Specific labelling of a component polypeptide of the oxidase. Biochem J 237:111–116 Cross AR, Jones OT (1991) Enzymic mechanisms of superoxide production. Biochim Biophys Acta 1057:281–298 Cucoranu I, Clempus R, Dikalova A, Phelan PJ, Ariyan S, Dikalov S, Sorescu D (2005) NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res 97:900–907 D’Angio CT, Finkelstein JN (2000) Oxygen regulation of gene expression: a study in opposites. Mol Genet Metab 71:371–380 Dahan I, Issaeva I, Gorzalczany Y, Sigal N, Hirshberg M, Pick E (2002) Mapping of functional domains in the p22(phox) subunit of flavocytochrome b(559) participating in the assembly of the NADPH oxidase complex by “peptide walking”. J Biol Chem 277:8421–8432 Davidge ST (1998) Oxidative stress and altered endothelial cell function in preeclampsia. Semin Reprod Endocrinol 16:65–73 de Carvalho DD, Sadok A, Bourgarel-Rey V, Gattacceca F, Penel C, Lehmann M, Kovacic H (2008) Nox1 downstream of 12-lipoxygenase controls cell proliferation but not cell spreading of colon cancer cells. Int J Cancer 122:1757–1764 De Minicis S, Brenner DA (2007) NOX in liver fibrosis. Arch Biochem Biophys 462:266–272 dela Pena A, Leclercq IA, Williams J, Farrell GC (2007) NADPH oxidase is not an essential mediator of oxidative stress or liver injury in murine MCD diet-induced steatohepatitis. J Hepatol 46:304–313 DeLeo F, Yu L, Burritt J, Loetterle L, Bond C, Jesaitis A, Quinn M (1995) Mapping sites of interaction of p47-phox and flavocytochrome b with random-sequence peptide phage display libraries. Proc Natl Acad Sci USA 92:7110–7114 DeLeo FR, Nauseef WM, Jesaitis AJ, Burritt JB, Clark RA, Quinn MT (1995) A domain of p47phox that interacts with human neutrophil flavocytochrome b558. J Biol Chem 270:26246–26251 DeLeo FR, Quinn MT (1996) Assembly of the phagocyte NADPH oxidase: molecular interaction of oxidase proteins. J Leukoc Biol 60:677–691 Deliri H, McNamara CA (2007) Nox 4 regulation of vascular smooth muscle cell differentiation marker gene expression. Arterioscler Thromb Vasc Biol 27:12–14 Demidchik V, Shabala SN, Coutts KB, Tester MA, Davies JM (2003) Free oxygen radicals regulate plasma membrane Ca2+- and K+-permeable channels in plant root cells. J Cell Sci 116:81–88 Deng S, Kruger A, Kleschyov AL, Kalinowski L, Daiber A, Wojnowski L (2007) Gp91phox-containing NAD(P)H oxidase increases superoxide formation by doxorubicin and NADPH. Free Radic Biol Med 42:466–473 Dharajiya N, Choudhury BK, Bacsi A, Boldogh I, Alam R, Sur S (2007) Inhibiting pollen reduced nicotinamide adenine dinucleotide phosphate oxidase-induced signal by intrapulmonary administration of antioxidants blocks allergic airway inflammation. J Allergy Clin Immunol 119:646–653 Diatchuk V, Lotan O, Koshkin V, Wikstroem P, Pick E (1997) Inhibition of NADPH oxidase activation by 4-(2-aminoethyl)-benzenesulfonyl fluoride and related compounds. J Biol Chem 272:13292–13301 Doerries C, Grote K, Hilfiker-Kleiner D, Luchtefeld M, Schaefer A, Holland SM, Sorrentino S, Manes C, Schieffer B, Drexler H, Landmesser U (2007) Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction. Circ Res 100:894–903 Dourron HM, Jacobson GM, Park JL, Liu J, Reddy DJ, Scheel ML, Pagano PJ (2005) Perivascular gene transfer of NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery. Am J Physiol Heart Circ Physiol 288:H946–H953 Doussiere J, Gaillard J, Vignais PV (1999) The heme component of the neutrophil NADPH oxidase complex is a target for aryliodonium compounds. Biochemistry 38:3694–3703 Doussiere J, Vignais PV (1992) Diphenylene iodonium as an inhibitor of the NADPH oxidase complex of bovine neutrophils. Factors controlling the inhibitory potency of diphenylene iodonium in a cell-free system of oxidase activation. Eur J Biochem 208:61–71 Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95 Dusting GJ, Selemidis S, Jiang F (2005) Mechanisms for suppressing NADPH oxidase in the vascular wall. Mem Inst Oswaldo Cruz 100(Suppl 1):97–103 Laurent E, McCoy JW, Macina RA, Liu W, Cheng G, Robine S, Papkoff J, Lambeth JD (2008) Nox1 is over-expressed in human colon cancers and correlates with activating mutations in K-Ras. Int J Cancer 123: 100–107 Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99 El Jamali A, Valente AJ, Lechleiter JD, Gamez MJ, Pearson DW, Nauseef WM, Clark RA (2008) Novel redox-dependent regulation of Nox5 NADPH oxidase by the non-receptor tyrosine kinase c-Abl. Free Radic Biol Med 44:868–881 Ellmark SH, Dusting GJ, Fui MN, Guzzo-Pernell N, Drummond GR (2005) The contribution of Nox4 to NADPH oxidase activity in mouse vascular smooth muscle. Cardiovasc Res 65:495–504 Ernst P (1999) Review article: the role of inflammation in the pathogenesis of gastric cancer. Aliment Pharmacol Ther 13(Suppl 1):13–18 Etoh T, Inoguchi T, Kakimoto M, Sonoda N, Kobayashi K, Kuroda J, Sumimoto H, Nawata H (2003) Increased expression of NAD(P)H oxidase subunits, NOX4 and p22phox, in the kidney of streptozotocin-induced diabetic rats and its reversibity by interventive insulin treatment. Diabetologia 46:1428–1437 Faggioni R, Gatti S, Demitri MT, Delgado R, Echtenacher B, Gnocchi P, Heremans H, Ghezzi P (1994) Role of xanthine oxidase and reactive oxygen intermediates in LPS- and TNF-induced pulmonary edema. J Lab Clin Med 123:394–399 Festjens N, Vanden Berghe T, Vandenabeele P (2006) Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 1757:1371–87 Finkel T (2001) Reactive oxygen species and signal transduction. IUBMB Life 52:3–6 Fridovich I (1999) Fundamental aspects of reactive oxygen species, or what’s the matter with oxygen? Ann N Y Acad Sci 893:13–18 Fridovich I (1997) Superoxide anion radical (O2 −), superoxide dismutases, and related matters. J Biol Chem 272:18515–18517 Fu NY, Zhang EX, Lin ZF, Yu LJ (1999) Relationship between superoxide anion radical and anion transport protein of red blood cell membrane. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 31:328–330 Fu X, Beer DG, Behar J, Wands J, Lambeth D, Cao W (2006) cAMP-response element-binding protein mediates acid-induced NADPH oxidase NOX5-S expression in Barrett esophageal adenocarcinoma cells. J Biol Chem 281:20368–20382 Fukuyama M, Rokutan K, Sano T, Miyake H, Shimada M, Tashiro S (2005) Overexpression of a novel superoxide-producing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colon. Cancer Lett 221:97–104 Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761 Gabrielli A, Svegliati S, Moroncini G, Luchetti M, Tonnini C, Avvedimento EV (2007) Stimulatory autoantibodies to the PDGF receptor: A link to fibrosis in scleroderma and a pathway for novel therapeutic targets. Autoimmun Rev 7:121–126 Gao XP, Standiford TJ, Rahman A, Newstead M, Holland SM, Dinauer MC, Liu QH, Malik AB (2002) Role of NADPH oxidase in the mechanism of lung neutrophil sequestration and microvessel injury induced by Gram-negative sepsis: studies in p47phox−/− and gp91phox−/− mice. J Immunol 168:3974–3982 Garvin JL, Ortiz PA (2003) The role of reactive oxygen species in the regulation of tubular function. Acta Physiol Scand 179:225–232 Gavazzi G, Banfi B, Deffert C, Fiette L, Schappi M, Herrmann F, Krause KH (2006) Decreased blood pressure in NOX1-deficient mice. FEBS Lett 580:497–504 Geiszt M, Kopp JB, Varnai P, Leto TL (2000) Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci USA 97:8010–8014 Geiszt M, Lekstrom K, Brenner S, Hewitt SM, Dana R, Malech HL, Leto TL (2003) NAD(P)H oxidase 1, a product of differentiated colon epithelial cells, can partially replace glycoprotein 91(phox) in the regulated production of superoxide by phagocytes. J Immunol 171:299–306 Geyer O, Podos SM, Mittag T (1997) Nitric oxide synthase activity in tissues of the bovine eye. Graefes Arch Clin Exp Ophthalmol 235:786–793 Gonzalez-Quintero VH, Jimenez JJ, Jy W, Mauro LM, Hortman L, O’Sullivan MJ, Ahn Y (2003) Elevated plasma endothelial microparticles in preeclampsia. Am J Obstet Gynecol 189:589–593 Gonzalez-Quintero VH, Smarkusky LP, Jimenez JJ, Mauro LM, Jy W, Hortsman LL, O’Sullivan MJ, Ahn YS (2004) Elevated plasma endothelial microparticles: preeclampsia versus gestational hypertension. Am J Obstet Gynecol 191:1418–1424 Gorin Y, Block K, Hernandez J, Bhandari B, Wagner B, Barnes JL, Abboud HE (2005) Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J Biol Chem 280:39616–39626 Goswami SK, Maulik N, Das DK (2007) Ischemia-reperfusion and cardioprotection: a delicate balance between reactive oxygen species generation and redox homeostasis. Ann Med 39:275–289 Govindarajan B, Sligh JE, Vincent BJ, Li M, Canter JA, Nickoloff BJ, Rodenburg RJ, Smeitink JA, Oberley L, Zhang Y, Slingerland J, Arnold RS, Lambeth JD, Cohen C, Hilenski L, Griendling K, Martinez-Diez M, Cuezva JM, Arbiser JL (2007) Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J Clin Invest 117:719–729 Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M, Campuzano V, Barbacid M (2003) Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4:111–120 Habibi J, Whaley-Connell A, Qazi MA, Hayden MR, Cooper SA, Tramontano A, Thyfault J, Stump C, Ferrario C, Muniyappa R, Sowers JR (2007) Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats. Endocrinology 148:2181–2188 Harada H, Hines IN, Flores S, Gao B, McCord J, Scheerens H, Grisham MB (2004) Role of NADPH oxidase-derived superoxide in reduced size liver ischemia and reperfusion injury. Arch Biochem Biophys 423:103–108 Harada N, Iimuro Y, Nitta T, Yoshida M, Uchinami H, Nishio T, Hatano E, Yamamoto N, Yamamoto Y, Yamaoka Y (2003) Inactivation of the small GTPase Rac1 protects the liver from ischemia/reperfusion injury in the rat. Surgery 134:480–491 Harraz MM, Marden JJ, Zhou W, Zhang Y, Williams A, Sharov VS, Nelson K, Luo M, Paulson H, Schoneich C, Engelhardt JF (2008) SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest 118:659–670 Henderson BC, Sen U, Reynolds C, Moshal KS, Ovechkin A, Tyagi N, Kartha GK, Rodriguez WE, Tyagi SC (2007) Reversal of systemic hypertension-associated cardiac remodeling in chronic pressure overload myocardium by ciglitazone. Int J Biol Sci 3:385–392 Heumuller S, Wind S, Barbosa-Sicard E, Schmidt HH, Busse R, Schroder K, Brandes RP (2008) Apocynin is not an inhibitor of vascular reduced nicotinamide-adenine dinucleotide phosphate oxidases but an antioxidant. Hypertension 51:211–217 Heymes C, Bendall JK, Ratajczak P, Cave AC, Samuel JL, Hasenfuss G, Shah AM (2003) Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol 41:2164–2171 Hines IN, Hoffman JM, Scheerens H, Day BJ, Harada H, Pavlick KP, Bharwani S, Wolf R, Gao B, Flores S, McCord JM, Grisham MB (2003) Regulation of postischemic liver injury following different durations of ischemia. Am J Physiol Gastrointest Liver Physiol 284:G536–G545 Hingtgen SD, Tian X, Yang J, Dunlay SM, Peek AS, Wu Y, Sharma RV, Engelhardt JF, Davisson RL (2006) Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy. Physiol Genomics 26:180–191 Holland JA, O’Donnell RW, Chang MM, Johnson DK, Ziegler LM (2000) Endothelial cell oxidant production: effect of NADPH oxidase inhibitors. Endothelium 7:109–119 Hougee S, Hartog A, Sanders A, Graus YM, Hoijer MA, Garssen J, van den Berg WB, van Beuningen HM, Smit HF (2006) Oral administration of the NADPH-oxidase inhibitor apocynin partially restores diminished cartilage proteoglycan synthesis and reduces inflammation in mice. Eur J Pharmacol 531:264–269 Hu R, Wang YL, Edderkaoui M, Lugea A, Apte MV, Pandol SJ (2007) Ethanol augments PDGF-induced NADPH oxidase activity and proliferation in rat pancreatic stellate cells. Pancreatology 7:332–340 Hultqvist M, Olofsson P, Gelderman KA, Holmberg J, Holmdahl R (2006) A new arthritis therapy with oxidative burst inducers. PLoS Med 3:e348 Ibi M, Katsuyama M, Fan C, Iwata K, Nishinaka T, Yokoyama T, Yabe-Nishimura C (2006) NOX1/NADPH oxidase negatively regulates nerve growth factor-induced neurite outgrowth. Free Radic Biol Med 40:1785–1795 Ishii N, Ishii T, Hartman PS (2007) The role of the electron transport SDHC gene on lifespan and cancer. Mitochondrion 7:24–28 Ishii T, Yasuda K, Akatsuka A, Hino O, Hartman PS, Ishii N (2005) A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis. Cancer Res 65:203–209 Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86 Jacobson GM, Dourron HM, Liu J, Carretero OA, Reddy DJ, Andrzejewski T, Pagano PJ (2003) Novel NAD(P)H oxidase inhibitor suppresses angioplasty-induced superoxide and neointimal hyperplasia of rat carotid artery. Circ Res 92:637–643 Jaeschke H, Mitchell JR (1989) Mitochondria and xanthine oxidase both generate reactive oxygen species in isolated perfused rat liver after hypoxic injury. Biochem Biophys Res Commun 160:140–147 Jeremy JY, Jones RA, Koupparis AJ, Hotston M, Persad R, Angelini GD, Shukla N (2007) Reactive oxygen species and erectile dysfunction: possible role of NADPH oxidase. Int J Impot Res 19:265–280 Jiang F, Drummond GR, Dusting GJ (2004) Suppression of oxidative stress in the endothelium and vascular wall. Endothelium 11:79–88 Jiang Q, Zhou C, Healey S, Chu W, Kouttab N, Bi Z, Wan Y (2006) UV radiation down-regulates Dsg-2 via Rac/NADPH oxidase-mediated generation of ROS in human lens epithelial cells. Int J Mol Med 18:381–387 Jin L, Burnett AL (2008) NADPH oxidase: recent evidence for its role in erectile dysfunction. Asian J Androl 10:6–13 Johar S, Cave AC, Narayanapanicker A, Grieve DJ, Shah AM (2006) Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. Faseb J 20:1546–8 Johnson DK, Schillinger KJ, Kwait DM, Hughes CV, McNamara EJ, Ishmael F, O’Donnell RW, Chang MM, Hogg MG, Dordick JS, Santhanam L, Ziegler LM, Holland JA (2002) Inhibition of NADPH oxidase activation in endothelial cells by ortho-methoxy-substituted catechols. Endothelium 9:191–203 Kamata H, Hirata H (1999) Redox regulation of cellular signalling. Cell Signal 11:1–14 Keenan JI, Peterson RA 2nd, Hampton MB (2005) NADPH oxidase involvement in the pathology of Helicobacter pylori infection. Free Radic Biol Med 38:1188–1196 Kim JS, Jin Y, Lemasters JJ (2006) Reactive oxygen species, but not Ca2+ overloading, trigger pH- and mitochondrial permeability transition-dependent death of adult rat myocytes after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 290:H2024–H2034 Kim YM, Guzik TJ, Zhang YH, Zhang MH, Kattach H, Ratnatunga C, Pillai R, Channon KM, Casadei B (2005) A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res 97:629–636 Kim YS, Morgan MJ, Choksi S, Liu ZG (2007) TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell 26:675–687 Kleinberg ME, Malech HL, Rotrosen D (1990) The phagocyte 47-kilodalton cytosolic oxidase protein is an early reactant in activation of the respiratory burst. J Biol Chem 265:15577–15583 Kobayashi S, Nojima Y, Shibuya M, Maru Y (2004) Nox1 regulates apoptosis and potentially stimulates branching morphogenesis in sinusoidal endothelial cells. Exp Cell Res 300:455–462 Kojda G, Harrison D (1999) Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 43:562–571 Kono H, Rusyn I, Uesugi T, Yamashina S, Connor HD, Dikalova A, Mason RP, Thurman RG (2001) Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat. Am J Physiol Gastrointest Liver Physiol 280:G1005–G1012 Kono H, Rusyn I, Yin M, Gabele E, Yamashina S, Dikalova A, Kadiiska MB, Connor HD, Mason RP, Segal BH, Bradford BU, Holland SM, Thurman RG (2000) NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest 106:867–872 Kourie JI (1998) Interaction of reactive oxygen species with ion transport mechanisms. Am J Physiol 275:C1–C24 Krause KH (2007) Aging: a revisited theory based on free radicals generated by NOX family NADPH oxidases. Exp Gerontol 42:256–262 Kuehl FA, Humes JL, Ham EA, Egan RW, Dougherty HW (1980) Inflammation: the role of peroxidase-derived products. Adv Prost Thromb Res 6:77–86 Kusaka I, Kusaka G, Zhou C, Ishikawa M, Nanda A, Granger DN, Zhang JH, Tang J (2004) Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. Am J Physiol Heart Circ Physiol 286:H2442–H2451 Lagente V, Planquois JM, Leclerc O, Schmidlin F, Bertrand CP (2008) Oxidative stress is an important component of airway inflammation in mice exposed to cigarette smoke or lipopolysaccharide. Clin Exp Pharmacol Physiol 35:601–605 Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189 Lambeth JD (2007) Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med 43:332–347 Lambeth JD (2000) Regulation of the phagocyte respiratory burst oxidase by protein interactions. J Biochem Mol Biol 33:427–439 Lambeth JD, Kawahara T, Diebold B (2007) Regulation of Nox and Duox enzymatic activity and expression. Free Radic Biol Med 43:319–331 Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, Holland SM, Harrison DG (2002) Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40:511–515 Larios JM, Budhiraja R, Fanburg BL, Thannickal VJ (2001) Oxidative protein cross-linking reactions involving l-tyrosine in transforming growth factor-beta1-stimulated fibroblasts. J Biol Chem 276:17437–17441 Lee AC, Fenster BE, Ito H, Takeda K, Bae NS, Hirai T, Yu ZX, Ferrans VJ, Howard BH, Finkel T (1999) Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem 274:7936–7940 Lee NK, Choi YG, Baik JY, Han SY, Jeong DW, Bae YS, Kim N, Lee SY (2005) A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106:852–859 Lee S-R, Kwon K-S, Kim S-R, Rhee SG (1998) Reversible inactivation of protein tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. Journal of Biological Chemistry 273:15366–15372 Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG (2002) Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 277:20336–20342 Lee VM, Quinn PA, Jennings SC, Ng LL (2003) NADPH oxidase activity in preeclampsia with immortalized lymphoblasts used as models. Hypertension 41:925–931 Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324 Li J, Stouffs M, Serrander L, Banfi B, Bettiol E, Charnay Y, Steger K, Krause KH, Jaconi ME (2006) The NADPH oxidase NOX4 drives cardiac differentiation: role in regulating cardiac transcription factors and MAP kinase activation. Mol Biol Cell 17:3978–3988 Li JM, Gall NP, Grieve DJ, Chen M, Shah AM (2002) Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. Hypertension 40:477–484 Littauer A, de Groot H (1992) Release of reactive oxygen by hepatocytes on reoxygenation: three phases and role of mitochondria. Am J Physiol 262:G1015–G1020 Looi YH, Grieve DJ, Siva A, Walker SJ, Anilkumar N, Cave AC, Marber M, Monaghan MJ, Shah AM (2008) Involvement of Nox2 NADPH oxidase in adverse cardiac remodeling after myocardial infarction. Hypertension 51:319–325 Maack C, Kartes T, Kilter H, Schafers HJ, Nickenig G, Bohm M, Laufs U (2003) Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment. Circulation 108:1567–1574 Maeda H, Akaike T (1998) Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc) 63:854–865 Mahadev K, Motoshima H, Wu X, Ruddy JM, Arnold RS, Cheng G, Lambeth JD, Goldstein BJ (2004) The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol 24:1844–1854 Malech JL, Gallin JI (1987) Immunology of neutrophils in human diseases. N Engl J Med 317:687–694 Maranchie JK, Zhan Y (2005) Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel–Lindau-deficient renal cell carcinoma. Cancer Res 65:9190–9193 Marden JJ, Harraz MM, Williams AJ, Nelson K, Luo M, Paulson H, Engelhardt JF (2007) Redox modifier genes in amyotrophic lateral sclerosis in mice. J Clin Invest 117:2913–2919 Marriott HM, Jackson LE, Wilkinson TS, Simpson AJ, Mitchell TJ, Buttle DJ, Cross SS, Ince PG, Hellewell PG, Whyte MK, Dockrell DH (2008) Reactive oxygen species regulate neutrophil recruitment and survival in pneumococcal pneumonia. Am J Respir Crit Care Med 177:887–895 Masamune A, Watanabe T, Kikuta K, Satoh K, Shimosegawa T (2008) NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells. Am J Phys Gastrointest Liver Physiol 294:G99–G108 Matsuno K, Yamada H, Iwata K, Jin D, Katsuyama M, Matsuki M, Takai S, Yamanishi K, Miyazaki M, Matsubara H, Yabe-Nishimura C (2005) Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation 112:2677–2685 Maytin M, Siwik DA, Ito M, Xiao L, Sawyer DB, Liao R, Colucci WS (2004) Pressure overload-induced myocardial hypertrophy in mice does not require gp91phox. Circulation 109:1168–1171 McCormick ML, Gavrila D, Weintraub NL (2007) Role of oxidative stress in the pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 27:461–469 Mehta PK, Griendling KK (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292:C82–C97 Meier B, Cross AR, Hancock JT, Kaup FJ, Jones OT (1991) Identification of a superoxide-generating NADPH oxidase system in human fibroblasts. Biochem J 275(Pt 1):241–245 Meneghin A, Hogaboam CM (2007) Infectious disease, the innate immune response, and fibrosis. J Clin Invest 117:530–538 Meng TC, Fukada T, Tonks NK (2002) Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell 9:387–399 Meyer M, Pahl HL, Baeuerle PA (1994) Regulation of the transcription factors NF-kappa B and AP-1 by redox changes. Chem Biol Interact 91:91–100 Mignotte B, Vayssiere JL (1998) Mitochondria and apoptosis. Eur J Biochem 252:1–15 Miriyala S, Gongora Nieto MC, Mingone C, Smith D, Dikalov S, Harrison DG, Jo H (2006) Bone morphogenic protein-4 induces hypertension in mice: role of noggin, vascular NADPH oxidases, and impaired vasorelaxation. Circulation 113:2818–2825 Mitsushita J, Lambeth JD, Kamata T (2004) The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transformation. Cancer res. 64:3580–3585 Mittal M, Roth M, Konig P, Hofmann S, Dony E, Goyal P, Selbitz AC, Schermuly RT, Ghofrani HA, Kwapiszewska G, Kummer W, Klepetko W, Hoda MA, Fink L, Hanze J, Seeger W, Grimminger F, Schmidt HH, Weissmann N (2007) Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 101:258–267 Mochizuki T, Furuta S, Mitsushita J, Shang WH, Ito M, Yokoo Y, Yamaura M, Ishizone S, Nakayama J, Konagai A, Hirose K, Kiyosawa K, Kamata T (2006) Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Oncogene 25:3699–3707 Mofarrahi M, Brandes RP, Gorlach A, Hanze J, Terada LS, Quinn MT, Mayaki D, Petrof B, Hussain SN (2008) Regulation of proliferation of skeletal muscle precursor cells by NADPH oxidase. Antioxid Redox Signal 10:559–574 Moraes TJ, Zurawska JH, Downey GP (2006) Neutrophil granule contents in the pathogenesis of lung injury. Curr Opin Hematol 13:21–27 Moreno JC, Visser TJ (2007) New phenotypes in thyroid dyshormonogenesis: hypothyroidism due to DUOX2 mutations. Endocr Dev 10:99–117 Morgan D, Oliveira-Emilio HR, Keane D, Hirata AE, Santos da Rocha M, Bordin S, Curi R, Newsholme P, Carpinelli AR (2007) Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line. Diabetologia 50:359–69 Morozov I, Lotan O, Joseph G, Gorzalczany Y, Pick E (1998) Mapping of functional domains in p47(phox) involved in the activation of NADPH oxidase by “peptide walking”. J Biol Chem 273:15435–15444 Nakagami H, Takemoto M, Liao JK (2003) NADPH oxidase-derived superoxide anion mediates angiotensin II-induced cardiac hypertrophy. J Mol Cell Cardiol 35:851–859 Nauseef WM (2004) Assembly of the phagocyte NADPH oxidase. Histochem Cell Biol 122:277–91 Nauseef WM, McCormick S, Renee J, Leidal KG, Clark RA (1993) Functional domain in an arginine-rich carboxyl-terminal region of p47phox. J Biol Chem 268:23646–23651 Nohl H, Gille L, Kozlov A, Staniek K (2003) Are mitochondria a spontaneous and permanent source of reactive oxygen species? Redox Rep 8:135–141 Nohl H, Gille L, Staniek K (2005) Intracellular generation of reactive oxygen species by mitochondria. Biochem Pharmacol 69:719–723 Nozik-Grayck E, Huang YC, Carraway MS, Piantadosi CA (2003) Bicarbonate-dependent superoxide release and pulmonary artery tone. Am J Physiol Heart Circ Physiol 285:H2327–H2335 Ohshiro Y, Ma RC, Yasuda Y, Hiraoka-Yamamoto J, Clermont AC, Isshiki K, Yagi K, Arikawa E, Kern TS, King GL (2006) Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase C{beta}-null mice. Diabetes 55:3112–3120 Oliveira HR, Verlengia R, Carvalho CR, Britto LR, Curi R, Carpinelli AR (2003) Pancreatic beta-cells express phagocyte-like NAD(P)H oxidase. Diabetes 52:1457–1463 Ozaki M, Deshpande S, Angkeow P, Bellan J, Lowenstein CJ, Dinauer MC, Goldschmidt-Clermont P, Suzuki S, Irani K (2001) Targeted inhibition of the small GTPase protects against ischemia/reperfusion liver injury in mice. Transplant Proc 33:863–864 Ozaki M, Deshpande SS, Angkeow P, Bellan J, Lowenstein CJ, Dinauer MC, Goldschmidt-Clermont PJ, Irani K (2000) Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo. FASEB J 14:418–429 Ozaki M, Irani K (2004) Measurement of in vivo oxidative stress regulated by the Rac1 GTPase. Methods Enzymol 381:184–191 Panaretakis T, Shabalina IG, Grander D, Shoshan MC, DePierre JW (2001) Reactive oxygen species and mitochondria mediate the induction of apoptosis in human hepatoma HepG2 cells by the rodent peroxisome proliferator and hepatocarcinogen, perfluorooctanoic acid. Toxicol Appl Pharmacol 173:56–64 Pannaccione A, Secondo A, Scorziello A, Cali G, Taglialatela M, Annunziato L (2005) Nuclear factor-kappaB activation by reactive oxygen species mediates voltage-gated K+ current enhancement by neurotoxic beta-amyloid peptides in nerve growth factor-differentiated PC-12 cells and hippocampal neurones. J Neurochem 94:572–586 Pantano C, Anathy V, Ranjan P, Heintz NH, Janssen-Heininger YM (2006) Non-phagocytic oxidase 1 causes death in lung epithelial cells via a TNF-R1-JNK signaling axis. Am J Respir Cell Mol Biol 36:473–479 Papa S, Skulachev VP (1997) Reactive oxygen species, mitochondria, apoptosis and aging. Mol Cell Biochem 174:305–319 Park HS, Chun JN, Jung HY, Choi C, Bae YS (2006) Role of NADPH oxidase 4 in lipopolysaccharide-induced proinflammatory responses by human aortic endothelial cells. Cardiovasc Res 72:447–455 Park HS, Lee SH, Park D, Lee JS, Ryu SH, Lee WJ, Rhee SG, Bae YS (2004) Sequential activation of phosphatidylinositol 3-kinase, beta Pix, Rac1, and Nox1 in growth factor-induced production of H2O2. Mol Cell Biol 24:4384–4394 Park L, Zhou P, Pitstick R, Capone C, Anrather J, Norris EH, Younkin L, Younkin S, Carlson G, McEwen BS, Iadecola C (2008) Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci USA 105:1347–1352 Patel DN, Bailey SR, Gresham JK, Schuchman DB, Shelhamer JH, Goldstein BJ, Foxwell BM, Stemerman MB, Maranchie JK, Valente AJ, Mummidi S, Chandrasekar B (2006) TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells. Biochem Biophys Res Commun 347:1113–1120 Patel M, Li QY, Chang LY, Crapo J, Liang LP (2005) Activation of NADPH oxidase and extracellular superoxide production in seizure-induced hippocampal damage. J Neurochem 92:123–31 Perry BN, Govindarajan B, Bhandarkar SS, Knaus UG, Valo M, Sturk C, Carrillo CO, Sohn A, Cerimele F, Dumont D, Losken A, Williams J, Brown LF, Tan X, Ioffe E, Yancopoulos GD, Arbiser JL (2006) Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice. J Invest Dermatol 126:2316–2322 Peshavariya HM, Dusting GJ, Selemidis S (2007) Analysis of dihydroethidium fluorescence for the detection of intracellular and extracellular superoxide produced by NADPH oxidase. Free Radic Res 41:699–712 Petry A, Djordjevic T, Weitnauer M, Kietzmann T, Hess J, Gorlach A (2006) NOX2 and NOX4 mediate proliferative response in endothelial cells. Antioxid Redox Signal 8:1473–1484 Proell V, Carmona-Cuenca I, Murillo MM, Huber H, Fabregat I, Mikulits W (2007) TGF-beta dependent regulation of oxygen radicals during transdifferentiation of activated hepatic stellate cells to myofibroblastoid cells. Comp Hepatol 6:1 Qin B, Cartier L, Dubois-Dauphin M, Li B, Serrander L, Krause KH (2005) A key role for the microglial NADPH oxidase in APP-dependent killing of neurons. Neurobiol Aging 27:1577–1587 Qin F, Simeone M, Patel R (2007) Inhibition of NADPH oxidase reduces myocardial oxidative stress and apoptosis and improves cardiac function in heart failure after myocardial infarction. Free Radic Biol Med 43:271–281 Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123–127 Raha S, Robinson BH (2001) Mitochondria, oxygen free radicals, and apoptosis. Am J Med Genet 106:62–70 Ranjan P, Anathy V, Burch PM, Weirather K, Lambeth JD, Heintz NH (2006) Redox-dependent expression of cyclin D1 and cell proliferation by Nox1 in mouse lung epithelial cells. Antioxid Redox Signal 8:1447–1459 Rao PV, Maddala R, John F, Zigler JS Jr (2004) Expression of nonphagocytic NADPH oxidase system in the ocular lens. Mol Vis 10:112–121 Reeves EP, Lu H, Jacobs HL, Messina CG, Bolsover S, Gabella G, Potma EO, Warley A, Roes J, Segal AW (2002) Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416:291–297 Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ (2001) Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(−) and systolic blood pressure in mice. Circ Res 89:408–414 Rigutto S, Hoste C, Dumont JE, Corvilain B, Miot F, De Deken X (2007) Duox1 is the main source of hydrogen peroxide in the rat thyroid cell line PCCl3. Exp Cell Res 313:3892–901 Ritsick DR, Edens WA, Finnerty V, Lambeth JD (2007) Nox regulation of smooth muscle contraction. Free Radic Biol Med 43:31–38 Rocic P, Lucchesi PA (2005) NAD(P)H oxidases and TGF-beta-induced cardiac fibroblast differentiation: Nox-4 gets Smad. Circ Res 97:850–852 Romero N, Denicola A, Souza JM, Radi R (1999) Diffusion of peroxynitrite in the presence of carbon dioxide. Arch Biochem Biophys 368:23–30 Rossary A, Arab K, Steghens JP (2007) Polyunsaturated fatty acids modulate NOX4 anion superoxide production in human fibroblasts. Biochem J 406:77–83 Russo MT, Blasi MF, Chiera F, Fortini P, Degan P, Macpherson P, Furuichi M, Nakabeppu Y, Karran P, Aquilina G, Bignami M (2004) The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic instability in mismatch repair-deficient cells. Mol Cell Biol 24:465–474 Sadok A, Bourgarel-Rey V, Gattacceca F, Penel C, Lehmann M, Kovacic H (2008) Nox1-dependent superoxide production controls colon adenocarcinoma cell migration. Biochim Biophys Acta 1783:23–33 Saeed SA, Waqar MA, Zubairi AJ, Bhurgri H, Khan A, Gowani SA, Waqar SN, Choudhary MI, Jalil S, Zaidi AH, Ara I (2005) Myocardial ischaemia and reperfusion injury: reactive oxygen species and the role of neutrophil. J Coll Physicians Surg Pak 15:507–514 Saito Y, Geisen P, Uppal A, Hartnett ME (2007) Inhibition of NAD(P)H oxidase reduces apoptosis and avascular retina in an animal model of retinopathy of prematurity. Mol Vis 13:840–853 Salles N, Szanto I, Herrmann F, Armenian B, Stumm M, Stauffer E, Michel JP, Krause KH (2005) Expression of mRNA for ROS-generating NADPH oxidases in the aging stomach. Exp Gerontol 40:353–357 Sangrar W, Gao Y, Scott M, Truesdell P, Greer PA (2007) Fer-mediated cortactin phosphorylation is associated with efficient fibroblast migration and is dependent on reactive oxygen species generation during integrin-mediated cell adhesion. Mol Cell Biol 27:6140–6152 Sankarapandi S, Zweier JL, Mukherjee G, Quinn MT, Huso DL (1998) Measurement and characterization of superoxide generation in microglial cells: evidence for an NADPH oxidase-dependent pathway. Arch Biochem Biophys 353:312–21 Satoh M, Ogita H, Takeshita K, Mukai Y, Kwiatkowski DJ, Liao JK (2006) Requirement of Rac1 in the development of cardiac hypertrophy. Proc Natl Acad Sci USA 103:7432–7437 Schappi M, Deffert C, Fiette L, Gavazzi G, Herrmann F, Belli D, Krause KH (2008) Branched fungal beta-glucan causes hyperinflammation and necrosis in phagocyte NADPH oxidase-deficient mice. J Pathol 214(4):434–444 Schroder K, Helmcke I, Palfi K, Krause KH, Busse R, Brandes RP (2007) Nox1 mediates basic fibroblast growth factor-induced migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 27:1736–1743 Segal AW, Abo A (1993) The biochemical basis of the NADPH oxidase of phagocytes. TIBS 18:43–47 Senft AP, Dalton TP, Nebert DW, Genter MB, Hutchinson RJ, Shertzer HG (2002) Dioxin increases reactive oxygen production in mouse liver mitochondria. Toxicol Appl Pharmacol 178:15–21 Serrander L, Cartier L, Bedard K, Banfi B, Lardy B, Plastre O, Sienkiewicz A, Forro L, Schlegel W, Krause KH (2007) NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J 406:105–114 Serrander L, Jaquet V, Bedard K, Plastre O, Hartley O, Arnaudeau S, Demaurex N, Schlegel W, Krause KH (2007) NOX5 is expressed at the plasma membrane and generates superoxide in response to protein kinase C activation. Biochimie 89:1159–1167 Shacter E, Weitzman SA (2002) Chronic inflammation and cancer. Oncology (Huntingt) 16:217–226, 229, discussion 230–2 Shi J, Ross CR, Leto TL, Blecha F (1996) PR-39, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase activity by binding to Src homology 3 domains of p47 phox. Proc Natl Acad Sci USA 93:6014–6018 Shibuya H, Ohkohchi N, Seya K, Satomi S (1997) Kupffer cells generate superoxide anions and modulate reperfusion injury in rat livers after cold preservation. Hepatology 25:356–360 Shiose A, Kuroda J, Tsuruya K, Hirai M, Hirakata H, Naito S, Hattori M, Sakaki Y, Sumimoto H (2001) A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem 276:1417–1423 Si J, Fu X, Behar J, Wands J, Beer DG, Souza RF, Spechler SJ, Lambeth D, Cao W (2007) NADPH oxidase NOX5-S mediates acid-induced cyclooxygenase-2 expression via activation of NF-kappaB in Barrett’s esophageal adenocarcinoma cells. J Biol Chem 282:16244–16255 Snelgrove RJ, Edwards L, Rae AJ, Hussell T (2006) An absence of reactive oxygen species improves the resolution of lung influenza infection. Eur J Immunol 36:1364–1373 Snelgrove RJ, Edwards L, Williams AE, Rae AJ, Hussell T (2006) In the absence of reactive oxygen species, T cells default to a Th1 phenotype and mediate protection against pulmonary Cryptococcus neoformans infection. J Immunol 177:5509–5516 Sorescu D, Griendling KK (2002) Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail 8:132–140 Sorescu GP, Song H, Tressel SL, Hwang J, Dikalov S, Smith DA, Boyd NL, Platt MO, Lassegue B, Griendling KK, Jo H (2004) 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 95:773–779 Staniek K, Nohl H (2000) Are mitochondria a permanent source of reactive oxygen species? Biochim Biophys Acta 1460:268–275 Stas S, Whaley-Connell A, Habibi J, Appesh L, Hayden MR, Karuparthi PR, Qazi M, Morris EM, Cooper SA, Link CD, Stump C, Hay M, Ferrario C, Sowers JR (2007) Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin–angiotensin–aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling. Endocrinology 148:3773–3780 Stielow C, Catar RA, Muller G, Wingler K, Scheurer P, Schmidt HH, Morawietz H (2006) Novel Nox inhibitor of oxLDL-induced reactive oxygen species formation in human endothelial cells. Biochem Biophys Res Commun 344:200–205 Stolk J, Hiltermann TJ, Dijkman JH, Verhoeven AJ (1994) Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am J Respir Cell Mol Biol 11:95–102 Strieter RM, Gomperts BN, Keane MP (2007) The role of CXC chemokines in pulmonary fibrosis. J Clin Invest 117:549–556 Stuehr DJ, Fasehun OA, Kwon NS, Gross SS, Gonzalez JA, Levi R, Nathan CF (1991) Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs. FASEB J 5:98–103 Sturrock A, Cahill B, Norman K, Huecksteadt TP, Hill K, Sanders K, Karwande SV, Stringham JC, Bull DA, Gleich M, Kennedy TP, Hoidal JR (2006) Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 290:L661–L673 Sturrock A, Huecksteadt TP, Norman K, Sanders K, Murphy TM, Chitano P, Wilson K, Hoidal JR, Kennedy TP (2007) Nox4 mediates TGF-beta1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292:L1543–L1555 Sumimoto H, Miyano K, Takeya R (2005) Molecular composition and regulation of the Nox family NAD(P)H oxidases. Biochem Biophys Res Commun 338:677–686 Suzuki Y, Wang W, Vu TH, Raffin TA (1992) Effect of NADPH oxidase inhibition on endothelial cell ELAM-1 mRNA expression. Biochem Biophys Res Commun 184:1339–1343 Suzuki YJ, Ford GD (1999) Redox regulation of signal transduction in cardiac and smooth muscle. J Mol Cell Cardiol 31:345–353 Szocs K, Lassegue B, Wenzel P, Wendt M, Daiber A, Oelze M, Meinertz T, Munzel T, Baldus S (2007) Increased superoxide production in nitrate tolerance is associated with NAD(P)H oxidase and aldehyde dehydrogenase 2 downregulation. J Mol Cell Cardiol 42:1111–1118 ten Freyhaus H, Huntgeburth M, Wingler K, Schnitker J, Baumer AT, Vantler M, Bekhite MM, Wartenberg M, Sauer H, Rosenkranz S (2006) Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. Cardiovasc Res 71:331–341 Teshima S, Kutsumi H, Kawahara T, Kishi K, Rokutan K (2000) Regulation of growth and apoptosis of cultured guinea pig gastric mucosal cells by mitogenic oxidase 1. Am J Physiol Gastrointest Liver Physiol 279:G1169–G1176 Teshima S, Rokutan K, Nikawa T, Kishi K (1998) Guinea pig gastric mucosal cells produce abundant superoxide anion through an NADPH oxidase-like system. Gastroenterology 115:1186–1196 Thabut G, El-Benna J, Samb A, Corda S, Megret J, Leseche G, Vicaut E, Aubier M, Boczkowski J (2002) Tumor necrosis factor-alpha increases airway smooth muscle oxidants production through a NADPH oxidase-like system to enhance myosin light chain phosphorylation and contractility. J Biol Chem 277:22814–22821 Thakur V, McMullen MR, Pritchard MT, Nagy LE (2007) Regulation of macrophage activation in alcoholic liver disease. J Gastroenterol Hepatol 221(Suppl):S53–S56 Thomas M, Gavrila D, McCormick ML, Miller FJ Jr, Daugherty A, Cassis LA, Dellsperger KC, Weintraub NL (2006) Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Circulation 114:404–413 Toledo-Pereyra LH, Lopez-Neblina F, Toledo AH (2004) Reactive oxygen species and molecular biology of ischemia/reperfusion. Ann Transplant 9:81–83 Tominaga K, Kawahara T, Sano T, Toida K, Kuwano Y, Sasaki H, Kawai T, Teshima-Kondo S, Rokutan K (2007) Evidence for cancer-associated expression of NADPH oxidase 1 (Nox1)-based oxidase system in the human stomach. Free Radic Biol Med 43:1627–1638 Touyz RM, Mercure C, He Y, Javeshghani D, Yao G, Callera GE, Yogi A, Lochard N, Reudelhuber TL (2005) Angiotensin II-dependent chronic hypertension and cardiac hypertrophy are unaffected by gp91phox-containing NADPH oxidase. Hypertension 45:530–537 Uchizono Y, Takeya R, Iwase M, Sasaki N, Oku M, Imoto H, Iida M, Sumimoto H (2006) Expression of isoforms of NADPH oxidase components in rat pancreatic islets. Life Sci 80:133–139 Uhlinger DJ, Tyagi SR, Lambeth JD (1995) On the mechanism of inhibition of the neutrophil respiratory burst oxidase by a peptide from the C-terminus of the large subunit of cytochrome b558. Biochemistry 34:524–527 Urakami H, Abe Y, Grisham MB (2007) Role of reactive metabolites of oxygen and nitrogen in partial liver transplantation: lessons learned from reduced-size liver ischaemia and reperfusion injury. Clin Exp Pharmacol Physiol 34:912–919 Ushio-Fukai M (2006) Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 71:226–235 Ushio-Fukai M (2007) VEGF signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal 9:731–739 Valencia A, Kochevar IE (2008) Nox1-based NADPH oxidase is the major source of UVA-induced reactive oxygen species in human keratinocytes. J Invest Dermatol 128:214–222 van der Vliet A (2008) NADPH oxidases in lung biology and pathology: host defense enzymes, and more. Free Radic Biol Med 44:938–955 Van Laethem A, Nys K, Van Kelst S, Claerhout S, Ichijo H, Vandenheede JR, Garmyn M, Agostinis P (2006) Apoptosis signal regulating kinase-1 connects reactive oxygen species to p38 MAPK-induced mitochondrial apoptosis in UVB-irradiated human keratinocytes. Free Radic Biol Med 41:1361–1371 Vanden Berghe T, Declercq W, Vandenabeele P (2007) NADPH oxidases: new players in TNF-induced necrotic cell death. Mol Cell 26:769–771 VanWijk MJ, Nieuwland R, Boer K, van der Post JA, VanBavel E, Sturk A (2002) Microparticle subpopulations are increased in preeclampsia: possible involvement in vascular dysfunction? Am J Obstet Gynecol 187:450–456 Vaquero EC, Edderkaoui M, Pandol SJ, Gukovsky I, Gukovskaya AS (2004) Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells. J Biol Chem 279:34643–34654 Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117:557–567 Vignais PV (2002) The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci 59:1428–1459 Vollgraf U, Wegner M, Richter-Landsberg C (1999) Activation of AP-1 and nuclear factor-kappaB transcription factors is involved in hydrogen peroxide-induced apoptotic cell death of oligodendrocytes. J Neurochem 73:2501–2509 Waghray M, Cui Z, Horowitz JC, Subramanian IM, Martinez FJ, Toews GB, Thannickal VJ (2005) Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J 19:854–856 Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M (2000) Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 20:61–69 Wagner B, Ricono JM, Gorin Y, Block K, Arar M, Riley D, Choudhury GG, Abboud HE (2007) Mitogenic signaling via platelet-derived growth factor beta in metanephric mesenchymal cells. J Am Soc Nephrol 18:2903–2911 Walder CE, Green SP, Darbonne WC, Mathias J, Rae J, Dinauer MC, Curnutte JT, Thomas GR (1997) Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. Stroke 28:2252–2258 Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488 Wang HD, Xu S, Johns DG, Du Y, Quinn MT, Cayatte AJ, Cohen RA (2001) Role of NADPH oxidase in the vascular hypertrophic and oxidative stress response to angiotensin II in mice. Circ Res 88:947–953 Wang P, Tang F, Li R, Zhang H, Chen S, Liu P, Huang H (2007) Contribution of different Nox homologues to cardiac remodeling in two-kidney two-clip renovascular hypertensive rats: effect of valsartan. Pharmacol Res 55:408–417 Wang Q, Tompkins KD, Simonyi A, Korthuis RJ, Sun AY, Sun GY (2006) Apocynin protects against global cerebral ischemia-reperfusion-induced oxidative stress and injury in the gerbil hippocampus. Brain Res 1090:182–189 Wang W, Suzuki Y, Tanigaki T, Rank DR, Raffin TA (1994) Effect of the NADPH oxidase inhibitor apocynin on septic lung injury in guinea pigs. Am J Respir Crit Care Med 150:1449–1452 Weiss SJ (1989) Tissue destruction by neutrophils. N Engl J Med 320:365–376 Whaley-Connell A, Habibi J, Nistala R, Cooper SA, Karuparthi PR, Hayden MR, Rehmer N, Demarco VG, Andresen BT, Wei Y, Ferrario C, Sowers R (2008) Attenuation of reduced nicotinamide-adenine dinucleotide phosphate oxidase activation and glomerular filtration barrier remodeling with statin treatment. Hypertension 51:474–480 Williams HC, Griendling KK (2007) NADPH oxidase inhibitors: new antihypertensive agents? J Cardiovasc Pharmacol 50:9–16 Winyard PG, Blake DR, Evans CH (2000) Free radicals and inflammation. Birkhèauser, Basel Wo YB, Zhu DY, Hu Y, Wang ZQ, Liu J, Lou YJ (2007) Reactive oxygen species involved in prenylflavonoids, icariin and icaritin, initiating cardiac differentiation of mouse embryonic stem cells. J Cell Biochem 103:1536–1550 Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A, Rosenberger A, Vonhof S, Bickeboller H, Toliat MR, Suk EK, Tzvetkov M, Kruger A, Seifert S, Kloess M, Hahn H, Loeffler M, Nurnberg P, Pfreundschuh M, Trumper L, Brockmoller J, Hasenfuss G (2005) NAD(P)H oxidase and multidrug resistance protein genetic polymor phisms are associated with doxorubicin-induced cardiotoxicity. Circulation 112:3754–762 Wu DC, Re DB, Nagai M, Ischiropoulos H, Przedborski S (2006) The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Natl Acad Sci USA 103:12132–12137 Wu S, Gao J, Dinh QT, Chen C, Fimmel S (2008) IL-8 production and AP-1 transactivation induced by UVA in human keratinocytes: roles of d-alpha-tocopherol. Mol Immunol 45:2288–2296 Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH (2007) Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res 67:10823–10830 Ximenes VF, Kanegae MP, Rissato SR, Galhiane MS (2007) The oxidation of apocynin catalyzed by myeloperoxidase: proposal for NADPH oxidase inhibition. Arch Biochem Biophys 457:134–141 Xu D, Rovira II, Finkel T (2002) Oxidants painting the cysteine chapel: redox regulation of PTPs. Dev Cell 2:251–252 Yang S, Ries WL, Key LL Jr (1998) Nicotinamide adenine dinucleotide phosphate oxidase in the formation of superoxide in osteoclasts. Calcif Tissue Int 63:346–350 Yang S, Zhang Y, Ries W, Key L (2004) Expression of Nox4 in osteoclasts. J Cell Biochem 92:238–248 Yin CC, Huang KT (2007) H2O2 but not O2 − elevated by oxidized LDL enhances human aortic smooth muscle cell proliferation. J Biomed Sci 14:245–254 Yu JH, Kim KH, Kim DG, Kim H (2007) Diphenyleneiodonium suppresses apoptosis in cerulein-stimulated pancreatic acinar cells. Int J Biochem Cell Biol 39:2063–2075 Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA (2006) Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55:2180–2191 Zekry D, Epperson TK, Krause KH (2003) A role for NOX NADPH oxidases in Alzheimer’s disease and other types of dementia. IUBMB Life 55:307–313 Zhang W, Wang M, Xie HY, Zhou L, Meng XQ, Shi J, Zheng S (2007) Role of reactive oxygen species in mediating hepatic ischemia-reperfusion injury and its therapeutic applications in liver transplantation. Transplant Proc 39:1332–1337 Zhang X, Shan P, Jiang G, Cohn L, Lee PJ (2006) Toll-like receptor 4 deficiency causes pulmonary emphysema. J Clin Invest 116:3050–3059