Advertisement

Mammalian NADPH Oxidases

  • Hélène BuvelotEmail author
  • Vincent Jaquet
  • Karl-Heinz Krause
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1982)

Abstract

Reactive oxygen species (ROS) are highly reactive oxygen derivatives. Initially, they were considered as metabolic by-products (of mitochondria in particular), which consistently lead to aging and disease. Over the last decades, however, it became increasingly apparent that virtually all eukaryotic cells possess specifically ROS-producing enzymes, namely, NOX NADPH oxidases. In most mammals, there are seven NOX isoforms: three closely related isoforms, NOX1, 2, 3, which are activated by cytoplasmic subunits; NOX4, which appears to be constitutively active; and the EF-hand-containing Ca2+-activated isoforms NOX5 and DUOX1 and 2. Loss-of-function mutations in NOX genes can lead to serious human disease. NOX2 deficiency leads to primary immune deficiency, while DUOX2 deficiency presents as congenital hypothyroidism. Nox-deficient mice provide important tools to explore the physiological functions of various NADPH oxidases as a loss of function in Nox2, Nox3, and Duox2 leads to a spontaneous phenotype. The genetic absence of Nox1, Nox4, and Duox1 does not result in an obvious mouse phenotype (the NOX5 gene is absent in rodents and can therefore not be studied using knockout mice). Since the discovery of the NOX family at the turn of the millennium, much progress in understanding the biochemistry and the physiology of NOX has been made; however many questions remain unanswered to date. This chapter is an overview of our present knowledge on mammalian NOX/DUOX enzymes.

Key words

NADPH oxidase Reactive oxygen species Redox signaling Genetic deficiency Mouse models 

Notes

Acknowledgment

This research was supported by the Swiss National Science Foundation program.

References

  1. 1.
    Warburg O (1908) Beobachtungen über die Oxydationsprozesse im Seeigelei. Hoppe-Seyler´s Z Für Physiol Chem 57:1–16CrossRefGoogle Scholar
  2. 2.
    Baldridge CW, Gerard RW (1932) The extra respiration of phagocytosis. Am J Physiol Content 103:235–236CrossRefGoogle Scholar
  3. 3.
    MacLeod J (1943) The role of oxygen in the metabolism and motility of human spermatozoa. Am J Physiol Content 138:512–518CrossRefGoogle Scholar
  4. 4.
    Iyer G, Islam M, Quastel J (1961) Biochemical Aspects of Phagocytosis. Nature 192:535–541CrossRefGoogle Scholar
  5. 5.
    Rossi F, Zatti M (1964) Biochemical aspects of phagocytosis in polymorphonuclear leucocytes. NADH and NADPH oxidation by the granules of resting and phagocytizing cells. Experientia 20:21–23PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Segal AW, Jones OT (1978) Novel cytochrome b system in phagocytic vacuoles of human granulocytes. Nature 276:515–517CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Segal AW, West I, Wientjes F et al (1992) Cytochrome b-245 is a flavocytochrome containing FAD and the NADPH-binding site of the microbicidal oxidase of phagocytes. Biochem J 284:781–788PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Royer-Pokora B, Kunkel LM, Monaco AP et al (1986) Cloning the gene for the inherited disorder chronic granulomatous disease on the basis of its chromosomal location. Cold Spring Harb Symp Quant Biol 51(Pt 1):177–183PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Lambeth J (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313CrossRefGoogle Scholar
  11. 11.
    Hajjar C, Cherrier MV, Mirandela GD et al (2017) The NOX family of proteins is also present in bacteria. mBio 8:e01487–e01417PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Heymes C, Bendall JK, Ratajczak P et al (2003) Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol 41:2164–2171PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Javesghani D, MAGDER SA, Barreiro E et al (2002) Molecular characterization of a superoxide-generating NAD (P) H oxidase in the ventilatory muscles. Am J Respir Crit Care Med 165:412–418PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Reinehr R, Becker S, Eberle A et al (2005) Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J Biol Chem 280:27179–27194PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Görlach A, Brandes RP, Nguyen K et al (2000) A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall. Circ Res 87:26–32PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Jones SA, O’Donnell VB, Wood JD et al (1996) Expression of phagocyte NADPH oxidase components in human endothelial cells. Am J Physiol-Heart Circ Physiol 271:H1626–H1634CrossRefGoogle Scholar
  17. 17.
    Li J-M, Shah AM (2002) Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells. J Biol Chem 277:19952–19960PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Nayernia Z, Colaianna M, Robledinos-Antón N et al (2017) Decreased neural precursor cell pool in NADPH oxidase 2-deficiency: from mouse brain to neural differentiation of patient derived iPSC. Redox Biol 13:82–93PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Piccoli C, Ria R, Scrima R, Cela O, D’Aprile A, Boffoli D et al (2005) Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells: novel evidence of the occurrence of NAD(P)H OXIDASE activity. J Biol Chem 280:26467–26476PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Borregaard N, Heiple JM, Simons ER et al (1983) Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation. J Cell Biol 97:52–61PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Heyworth PG, Bohl BP, Bokoch GM et al (1994) Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its interaction with flavocytochrome b558. J Biol Chem 269:30749–30752PubMedPubMedCentralGoogle Scholar
  22. 22.
    Koga H, Terasawa H, Nunoi H et al (1999) Tetratricopeptide repeat (TPR) motifs of p67(phox) participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase. J Biol Chem 274:25051–25060PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Buvelot H, Posfay-Barbe KM, Linder P et al (2017) Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease. FEMS Microbiol Rev 41:139–157PubMedPubMedCentralGoogle Scholar
  24. 24.
    Cachat J, Deffert C, Hugues S et al (2015) Phagocyte NADPH oxidase and specific immunity. Clin Sci 128:635–648PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Cabiscol E, Tamarit J, Ros J (2000) Oxidative stress in bacteria and protein damage by reactive oxygen species. Int Microbiol Off J Span Soc Microbiol 3:3–8Google Scholar
  26. 26.
    Bandyopadhyay U, Das D, Banerjee RK (1999) Reactive oxygen species: oxidative damage and pathogenesis. Curr Sci 77:658–666Google Scholar
  27. 27.
    Fontecave M, Ollagnier-de-Choudens S (2008) Iron-sulfur cluster biosynthesis in bacteria: mechanisms of cluster assembly and transfer. Arch Biochem Biophys 474:226–237PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Imlay JA (2014) The mismetallation of enzymes during oxidative stress. J Biol Chem 289:28121–28128PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Levine AP, Duchen MR, de Villiers S et al (2015) Alkalinity of neutrophil phagocytic vacuoles is modulated by HVCN1 and has consequences for myeloperoxidase activity. PLoS One 10:e0125906PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Elsen S, Doussière J, Villiers CL et al (2004) Cryptic O2 -generating NADPH oxidase in dendritic cells. J Cell Sci 117:2215–2226PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Mantegazza AR, Savina A, Vermeulen M et al (2008) NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells. Blood 112:4712–4722PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Fuchs TA, Abed U, Goosmann C et al (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Stoiber W, Obermayer A, Steinbacher P et al (2015) The Role of Reactive Oxygen Species (ROS) in the formation of Extracellular Traps (ETs) in humans. Biomolecules 5:702–723PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Yamamoto A, Taniuchi S, Tsuji S et al (2002) Role of reactive oxygen species in neutrophil apoptosis following ingestion of heat-killed Staphylococcus aureus. Clin Exp Immunol 129:479–484PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Kobayashi SD, Voyich JM, Braughton KR et al (2004) Gene expression profiling provides insight into the pathophysiology of chronic granulomatous disease. J Immunol 172:636–643PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Huang J, Canadien V, Lam GY et al (2009) Activation of antibacterial autophagy by NADPH oxidases. Proc Natl Acad Sci U S A 106:6226–6231PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    de Luca A, Smeekens SP, Casagrande A et al (2014) IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc Natl Acad Sci U S A 111:3526–3531PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Iles KE, Forman HJ (2002) Macrophage signaling and respiratory burst. Immunol Res 26:95–105PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Huang C-K, Zhan L, Hannigan MO et al (2000) P47phox -deficient NADPH oxidase defect in neutrophils of diabetic mouse strains, C57BL/6J-m db/db and db/+. J Leukoc Biol 67:210–215PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Nakano Y, Longo-Guess CM, Bergstrom DE et al (2008) Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice. J Clin Invest 118:1176–1185PubMedPubMedCentralGoogle Scholar
  41. 41.
    Pollock JD, Williams DA, Gifford MAC et al (1995) Mouse model of X–linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet 9:202–209PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Ellson CD, Davidson K, Ferguson GJ et al (2006) Neutrophils from p40phox-/- mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing. J Exp Med 203:1927–1937PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Jackson SH, Gallin JI, Holland SM (1995) The p47phox mouse knock-out model of chronic granulomatous disease. J Exp Med 182:751–758PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Jacob CO, Yu N, Yoo D-G et al (2017) Haploinsufficiency of NADPH oxidase subunit neutrophil cytosolic factor 2 is sufficient to accelerate full-blown lupus in NZM 2328 mice. Arthritis Rheumatol 69:1647–1660PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Messina CGM, Reeves EP, Roes J et al (2002) Catalase negative Staphylococcus aureus retain virulence in mouse model of chronic granulomatous disease. FEBS Lett 518:107–110PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Pizzolla A, Hultqvist M, Nilson B et al (2012) Reactive oxygen species produced by the NADPH oxidase 2 complex in monocytes protect mice from bacterial infections. J Immunol 188:5003–5011PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Deffert C, Carnesecchi S, Yuan H et al (2012) Hyperinflammation of chronic granulomatous disease is abolished by NOX2 reconstitution in macrophages and dendritic cells. J Pathol 228:341–350PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Mori M, Li G, Hashimoto M et al (2009) Pivotal advance: eosinophilia in the MES rat strain is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba). J Leukoc Biol 86:473–478PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Hultqvist M, Holmdahl R (2005) Ncf1 (p47phox) polymorphism determines oxidative burst and the severity of arthritis in rats and mice. Cell Immunol 233:97–101PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Bánfi B, Clark RA, Steger K et al (2003) Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J Biol Chem 278:3510–3513PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Suh YA, Arnold RS, Lassegue B et al (1999) Cell transformation by the superoxide-generating oxidase Mox1. Nature 401:79–82PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Szanto I, Rubbia-Brandt L, Kiss P et al (2005) Expression of NOX1, a superoxide-generating NADPH oxidase, in colon cancer and inflammatory bowel disease. J Pathol 207:164–176PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Lassègue B, Sorescu D, Szöcs K et al (2001) Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res 88:888–894PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Ago T, Kitazono T, Kuroda J et al (2005) NAD(P)H oxidases in rat basilar arterial endothelial cells. Stroke 36:1040–1046PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Kobayashi S, Nojima Y, Shibuya M et al (2004) Nox1 regulates apoptosis and potentially stimulates branching morphogenesis in sinusoidal endothelial cells. Exp Cell Res 300:455–462PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Cui X-L, Brockman D, Campos B et al (2006) Expression of NADPH oxidase isoform 1 (Nox1) in human placenta: involvement in preeclampsia. Placenta 27:422–431PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Katsuyama M, Fan C, Yabe-Nishimura C (2002) NADPH oxidase is involved in prostaglandin F2alpha-induced hypertrophy of vascular smooth muscle cells: induction of NOX1 by PGF2alpha. J Biol Chem 277:13438–13442PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Lee YS (2005) Role of NADPH oxidase-mediated generation of reactive oxygen species in the mechanism of apoptosis induced by phenolic acids in HepG2 human hepatoma cells. Arch Pharm Res 28:1183–1189PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Wingler K, Wünsch S, Kreutz R et al (2001) Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo. Free Radic Biol Med 31:1456–1464PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Plesková M, Beck K-F, Behrens MH et al (2006) Nitric oxide down-regulates the expression of the catalytic NADPH oxidase subunit Nox1 in rat renal mesangial cells. FASEB J 20:139–141PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Matsuno K, Yamada H, Iwata K et al (2005) Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation 112:2677–2685PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Gavazzi G, Banfi B, Deffert C et al (2006) Decreased blood pressure in NOX1-deficient mice. FEBS Lett 580:497–504PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Coant N, Ben Mkaddem S, Pedruzzi E et al (2010) NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon. Mol Cell Biol 30:2636–2650PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Rokutan K, Kawahara T, Kuwano Y et al (2006) NADPH oxidases in the gastrointestinal tract: a potential role of Nox1 in innate immune response and carcinogenesis. Antioxid Redox Signal 8:1573–1582PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Hayes P, Dhillon S, O’Neill K et al (2015) Defects in NADPH oxidase genes NOX1 and DUOX2 in very early onset inflammatory bowel disease. Cell Mol Gastroenterol Hepatol 1:489–502PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Schwerd T, Bryant RV, Pandey S et al (2018) NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunol 11(2):562–574PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Sobotta MC, Liou W, Stöcker S et al (2015) Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling. Nat Chem Biol 11:64–70PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Stöcker S, Maurer M, Ruppert T et al (2018) A role for 2-Cys peroxiredoxins in facilitating cytosolic protein thiol oxidation. Nat Chem Biol 14:148–155PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Kwon J, Wang A, Burke DJ et al (2016) Peroxiredoxin 6 (Prdx6) supports NADPH oxidase1 (Nox1)-based superoxide generation and cell migration. Free Radic Biol Med 96:99–115PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Woo HA, Yim SH, Shin DH et al (2010) Inactivation of peroxiredoxin I by phosphorylation allows localized H2O2 accumulation for cell signaling. Cell 140:517–528PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Alvarez LA, Kovačič L, Rodríguez J et al (2016) NADPH oxidase-derived H2O2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA. Proc Natl Acad Sci U S A 113:10406–10411PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Bánfi B, Malgrange B, Knisz J et al (2004) NOX3, a Superoxide-generating NADPH Oxidase of the Inner Ear. J Biol Chem 279:46065–46072PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Ueno N, Takeya R, Miyano K et al (2005) The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators. J Biol Chem 280:23328–23339PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Paffenholz R, Bergstrom RA, Pasutto F et al (2004) Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an NADPH oxidase. Genes Dev 18:486–491PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Kiss PJ, Knisz J, Zhang Y et al (2006) Inactivation of NADPH oxidase organizer 1 results in severe imbalance. Curr Biol CB 16:208–213PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Flaherty JP, Spruce CA, Fairfield HE et al (2010) Generation of a conditional null allele of NADPH oxidase activator 1 (NOXA1). Genesis 48:568–575PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Lavinsky J, Crow AL, Pan C et al (2015) Genome-wide Association Study identifies Nox3 as a critical gene for susceptibility to noise-induced hearing loss. PLoS Genet 11:e1005094PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Geiszt M, Kopp JB, Várnai P et al (2000) Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A 97:8010–8014PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Shiose A, Kuroda J, Tsuruya K et al (2001) A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem 276:1417–1423PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Yang S, Madyastha P, Bingel S et al (2001) A new superoxide-generating oxidase in murine osteoclasts. J Biol Chem 276:5452–5458PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Yang S, Zhang Y, Ries W et al (2004) Expression of Nox4 in osteoclasts. J Cell Biochem 92:238–248PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Hu T, Ramachandrarao SP, Siva S et al (2005) Reactive oxygen species production via NADPH oxidase mediates TGF-beta-induced cytoskeletal alterations in endothelial cells. Am J Physiol Renal Physiol 289:F816–F825PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Van Buul JD, Fernandez-Borja M, Anthony EC et al (2005) Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Antioxid Redox Signal 7:308–317PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Ellmark SHM, Dusting GJ, Fui MNT et al (2005) The contribution of Nox4 to NADPH oxidase activity in mouse vascular smooth muscle. Cardiovasc Res 65:495–504PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Hoidal JR, Brar SS, Sturrock AB et al (2003) The role of endogenous NADPH oxidases in airway and pulmonary vascular smooth muscle function. Antioxid Redox Signal 5:751–758PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Janiszewski M, Lopes LR, Carmo AO et al (2005) Regulation of NAD(P)H oxidase by associated protein disulfide isomerase in vascular smooth muscle cells. J Biol Chem 280:40813–40819PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Laude K, Cai H, Fink B et al (2005) Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice. Am J Physiol Heart Circ Physiol 288:H7–H12PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Pedruzzi E, Guichard C, Ollivier V et al (2004) NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol 24:10703–10717PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Chamulitrat W, Stremmel W, Kawahara T et al (2004) A constitutive NADPH oxidase-like system containing gp91phox homologs in human keratinocytes. J Invest Dermatol 122:1000–1009PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Brar SS, Kennedy TP, Sturrock AB et al (2002) An NAD(P)H oxidase regulates growth and transcription in melanoma cells. Am J Physiol Cell Physiol 282:C1212–C1224PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Nisimoto Y, Diebold BA, Constentino-Gomes D et al (2014) Nox4: a hydrogen peroxide-generating oxygen sensor. Biochemistry (Mosc) 53:5111–5120CrossRefGoogle Scholar
  92. 92.
    Serrander L, Cartier L, Bedard K et al (2007) NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J 406:105–114PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Lyle AN, Deshpande NN, Taniyama Y et al (2009) Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res 105:249–259PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Martyn KD, Frederick LM, von Loehneysen K et al (2006) Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal 18:69–82PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Takac I, Schröder K, Zhang L et al (2011) The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem 286:13304–13313PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Mittal M, Roth M, König P et al (2007) Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 101:258–267PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Pendyala S, Moitra J, Kalari S et al (2011) Nrf2 regulates hyperoxia-induced Nox4 expression in human lung endothelium: identification of functional antioxidant response elements on the Nox4 promoter. Free Radic Biol Med 50:1749–1759PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Sedeek M, Callera G, Montezano A et al (2010) 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 299:F1348–F1358PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Cunningham KS, Gotlieb AI (2005) The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 85:9–23PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Piera-Velazquez S, Makul A, Jiménez SA (2015) Increased expression of NAPDH oxidase 4 in systemic sclerosis dermal fibroblasts: regulation by transforming growth factor β. Arthritis Rheumatol 67:2749–2758PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Craige SM, Chen K, Pei Y et al (2011) NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation. Circulation 124:731–740PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Schröder K, Zhang M, Benkhoff S et al (2012) Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res 110:1217–1225PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Lozhkin A, Vendrov AE, Pan H et al (2017) NADPH oxidase 4 regulates vascular inflammation in aging and atherosclerosis. J Mol Cell Cardiol 102:10–21PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Casas AI, Geuss E, Kleikers PWM et al (2017) NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage. Proc Natl Acad Sci U S A 114:12315–12320PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Jiménez-Altayó F, Meirelles T, Crosas-Molist E, Sorolla MA, Del Blanco DG, López-Luque J et al (2018) Redox stress in Marfan syndrome: dissecting the role of the NADPH OXIDASE NOX4 in aortic aneurysm. Free Radic Biol Med 118:44–58PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Irani K (2000) Oxidant signaling in vascular cell growth, death, and survival: a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ Res 87:179–183PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Hampton MB, Orrenius S (1997) Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Lett 414:552–556PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Hampton MB, Fadeel B, Orrenius S (1998) Redox regulation of the caspases during apoptosis. Ann N Y Acad Sci 854:328–335PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Mochizuki T, Furuta S, Mitsushita J et al (2006) Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Oncogene 25:3699–3707PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Laurent A, Nicco C, Chéreau C et al (2005) Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res 65:948–956PubMedPubMedCentralGoogle Scholar
  111. 111.
    Colavitti R, Finkel T (2005) Reactive oxygen species as mediators of cellular senescence. IUBMB Life 57:277–281PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Hannken T, Schroeder R, Stahl RA et al (1998) Angiotensin II-mediated expression of p27Kip1 and induction of cellular hypertrophy in renal tubular cells depend on the generation of oxygen radicals. Kidney Int 54:1923–1933PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Imanishi T, Hano T, Nishio I (2005) Estrogen reduces angiotensin II-induced acceleration of senescence in endothelial progenitor cells. Hypertens Res 28:263–271PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Krause K-H (2007) Aging: a revisited theory based on free radicals generated by NOX family NADPH oxidases. Exp Gerontol 42:256–262PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Diebold I, Flügel D, Becht S et al (2010) The hypoxia-inducible factor-2alpha is stabilized by oxidative stress involving NOX4. Antioxid Redox Signal 13:425–436PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Chen K, Kirber MT, Xiao H et al (2008) Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol 181:1129–1139PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Prior K-K, Wittig I, Leisegang MS et al (2016) The endoplasmic reticulum chaperone calnexin is a NADPH oxidase NOX4 interacting protein. J Biol Chem 291:7045–7059PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Kleinschnitz C, Grund H, Wingler K et al (2010) Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol 8:e1000479PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Zhang M, Brewer AC, Schröder K et al (2010) NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci U S A 107:18121–18126PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Nlandu Khodo S, Dizin E, Sossauer G et al (2012) NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury. J Am Soc Nephrol 23:1967–1976PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Schürmann C, Rezende F, Kruse C et al (2015) The NADPH oxidase Nox4 has anti-atherosclerotic functions. Eur Heart J 36:3447–3456PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Goettsch C, Babelova A, Trummer O, et al NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis. https://www.jci.org/articles/view/67603/pdf
  125. 125.
    Bánfi B, Molnár G, Maturana A et al (2001) A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes. J Biol Chem 276:37594–37601PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Cheng G, Cao Z, Xu X et al (2001) Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 269:131–140CrossRefGoogle Scholar
  127. 127.
    Salles N, Szanto I, Herrmann F et al (2005) Expression of mRNA for ROS-generating NADPH oxidases in the aging stomach. Exp Gerontol 40:353–357PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Bánfi B, Tirone F, Durussel I et al (2004) Mechanism of Ca2+ activation of the NADPH oxidase 5 (NOX5). J Biol Chem 279:18583–18591PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Tirone F, Cox JA (2007) NADPH oxidase 5 (NOX5) interacts with and is regulated by calmodulin. FEBS Lett 581:1202–1208PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Jagnandan D, Church JE, Banfi B et al (2007) Novel mechanism of activation of NADPH oxidase 5. calcium sensitization via phosphorylation. J Biol Chem 282:6494–6507CrossRefGoogle Scholar
  131. 131.
    Kawahara T, Lambeth JD (2008) Phosphatidylinositol (4,5)-bisphosphate modulates Nox5 localization via an N-terminal polybasic region. Mol Biol Cell 19:4020–4031PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Guzik TJ, Chen W, Gongora MC et al (2008) Calcium-dependent NOX5 nicotinamide adenine dinucleotide phosphate oxidase contributes to vascular oxidative stress in human coronary artery disease. J Am Coll Cardiol 52:1803–1809PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Kleikers PWM, Dao VT, Göb E et al (2014) SFRR-E Young Investigator AwardeeNOXing out stroke: identification of NOX4 and 5as targets in blood-brain-barrier stabilisation and neuroprotection. Free Radic Biol Med 75(Suppl 1):S16PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Wang Y, Chen F, Le B et al (2014) Impact of Nox5 polymorphisms on basal and stimulus-dependent ROS generation. PLoS One 9:e100102PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Bedard K, Jaquet V, Krause K-H (2012) NOX5: from basic biology to signaling and disease. Free Radic Biol Med 52:725–734CrossRefGoogle Scholar
  136. 136.
    De Deken X, Wang D, Many MC et al (2000) Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem 275:23227–23233CrossRefGoogle Scholar
  137. 137.
    Forteza R, Salathe M, Miot F et al (2005) Regulated hydrogen peroxide production by Duox in human airway epithelial cells. Am J Respir Cell Mol Biol 32:462–469PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Geiszt M, Witta J, Baffi J et al (2003) Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J 17:1502–1504CrossRefGoogle Scholar
  139. 139.
    Schwarzer C, Machen TE, Illek B et al (2004) NADPH oxidase-dependent acid production in airway epithelial cells. J Biol Chem 279:36454–36461PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Grasberger H, El-Zaatari M, Dang DT et al (2013) Dual oxidases control release of hydrogen peroxide by the gastric epithelium to prevent Helicobacter felis infection and inflammation in mice. Gastroenterology 145:1045–1054PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Wang D, De Deken X, Milenkovic M et al (2005) Identification of a novel partner of duox: EFP1, a thioredoxin-related protein. J Biol Chem 280:3096–3103PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Ameziane-El-Hassani R, Morand S, Boucher J-L et al (2005) Dual oxidase-2 has an intrinsic Ca2+-dependent H2O2-generating activity. J Biol Chem 280:30046–30054PubMedCrossRefGoogle Scholar
  143. 143.
    Rigutto S, Hoste C, Grasberger H et al (2009) Activation of dual oxidases Duox1 and Duox2: differential regulation mediated by camp-dependent protein kinase and protein kinase C-dependent phosphorylation. J Biol Chem 284:6725–6734PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Aycan Z, Cangul H, Muzza M et al (2017) Digenic DUOX1 and DUOX2 mutations in cases with congenital hypothyroidism. J Clin Endocrinol Metab 102:3085–3090PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Dupuy C, Pomerance M, Ohayon R et al (2000) Thyroid oxidase (THOX2) gene expression in the rat thyroid cell line FRTL-5. Biochem Biophys Res Commun 277:287–292PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    El Hassani RA, Benfares N, Caillou B et al (2005) Dual oxidase2 is expressed all along the digestive tract. Am J Physiol Gastrointest Liver Physiol 288:G933–G942CrossRefGoogle Scholar
  147. 147.
    Parlato M, Charbit-Henrion F, Hayes P et al (2017) First identification of biallelic inherited DUOX2 inactivating mutations as a cause of very early onset inflammatory bowel disease. Gastroenterology 153:609–611.e3PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Dupuy C, Ohayon R, Valent A et al (1999) Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cdnas. J Biol Chem 274:37265–37269CrossRefGoogle Scholar
  149. 149.
    Moreno JC, Bikker H, Kempers MJE et al (2002) Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 347:95–102PubMedCrossRefGoogle Scholar
  150. 150.
    Carvalho DP, Dupuy C (2017) Thyroid hormone biosynthesis and release. Mol Cell Endocrinol 458:6–15PubMedCrossRefGoogle Scholar
  151. 151.
    Nie Y, Speakman JR, Wu Q et al (2015) ANIMAL PHYSIOLOGY. Exceptionally low daily energy expenditure in the bamboo-eating giant panda. Science 349:171–174PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Johnson KR, Marden CC, Ward-Bailey P et al (2007) Congenital hypothyroidism, dwarfism, and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 gene, Duox2. Mol Endocrinol Baltim Md 21:1593–1602CrossRefGoogle Scholar
  153. 153.
    Dupuy C, Virion A, Ohayon R et al (1991) Mechanism of hydrogen peroxide formation catalyzed by NADPH oxidase in thyroid plasma membrane. J Biol Chem 266:3739–3743PubMedPubMedCentralGoogle Scholar
  154. 154.
    Leseney AM, Dème D, Legué O et al (1999) Biochemical characterization of a Ca2+/NAD(P)H-dependent H2O2 generator in human thyroid tissue. Biochimie 81:373–380PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Nakamura Y, Ohtaki S, Makino R et al (1989) Superoxide anion is the initial product in the hydrogen peroxide formation catalyzed by NADPH oxidase in porcine thyroid plasma membrane. J Biol Chem 264:4759–4761PubMedPubMedCentralGoogle Scholar
  156. 156.
    Nakamura Y, Makino R, Tanaka T et al (1991) Mechanism of H2O2 production in porcine thyroid cells: evidence for intermediary formation of superoxide anion by NADPH-dependent H2O2-generating machinery. Biochemistry (Mosc) 30:4880–4886CrossRefGoogle Scholar
  157. 157.
    Hunter T (2000) Signaling--2000 and beyond. Cell 100:113–127PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Denu JM, Tanner KG (1998) Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry (Mosc) 37:5633–5642CrossRefGoogle Scholar
  159. 159.
    Leslie NR, Bennett D, Lindsay YE et al (2003) Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J 22:5501–5510PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Cui W, Matsuno K, Iwata K et al (2011) NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligation. Hepatol Baltim Md 54:949–958CrossRefGoogle Scholar
  161. 161.
    Hervera A, De Virgiliis F, Palmisano I et al (2018) Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat Cell Biol 20:307–319PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Carnesecchi S, Deffert C, Donati Y et al (2011) A key role for NOX4 in epithelial cell death during development of lung fibrosis. Antioxid Redox Signal 15:607–619PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Lan T, Kisseleva T, Brenner DA (2015) Deficiency of NOX1 or NOX4 prevents liver inflammation and fibrosis in mice through inhibition of hepatic stellate cell activation. PLoS One 10:e0129743PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Nayernia Z, Jaquet V, Krause K-H (2014) New insights on NOX enzymes in the central nervous system. Antioxid Redox Signal 20:2815–2837PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Sorce S, Stocker R, Seredenina T et al (2017) NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: what is the evidence? Free Radic Biol Med 112:387–396CrossRefGoogle Scholar
  166. 166.
    Di Marco E, Gray SP, Chew P et al (2016) Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE-/- mice. Clin Sci 130:1363–1374PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Aoyama T, Paik Y-H, Watanabe S et al (2012) Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 56:2316–2327PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Garrido-Urbani S, Jemelin S, Deffert C et al (2011) Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism. PLoS One 6:e14665PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Musset B, Clark RA, DeCoursey TE et al (2012) NOX5 in human spermatozoa: expression, function, and regulation. J Biol Chem 287:9376–9388PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Strengert M, Jennings R, Davanture S et al (2014) Mucosal reactive oxygen species are required for antiviral response: role of Duox in influenza a virus infection. Antioxid Redox Signal 20:2695–2709PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Schildknecht S, Weber A, Gerding HR et al (2014) The NOX1/4 inhibitor GKT136901 as selective and direct scavenger of peroxynitrite. Curr Med Chem 21:365–376PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Hirano K, Chen WS, Chueng ALW et al (2015) Discovery of GSK2795039, a novel small molecule NADPH oxidase 2 inhibitor. Antioxid Redox Signal 23:358–374PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Hélène Buvelot
    • 1
    Email author
  • Vincent Jaquet
    • 1
  • Karl-Heinz Krause
    • 1
  1. 1.Department of Pathology and Immunology, Faculty of MedicineUniversity of GenevaGenevaSwitzerland

Personalised recommendations