The human Nox4: Gene, structure, physiological function and pathological significance

Journal of Drug Targeting

Volumn 23, Issue 10, 2015, Pages 888-896

  Guo, Shuhui ^a   Chen, Xiuping ^a  

^a University of Macau   (Macao)

Author keywords

Cancer; cardiovascular diseases; hydrogen peroxides; Nox4; ROS

Indexed keywords

2 ETHYL 1,2,3,4,6,7 HEXAHYDRO 2 HYDROXY 3 ISOBUTYL 9,10 DIMETHOXY 11BH BENZO[A]QUINOLIZINE; BENZOTHIOPHENE; FLAVONOID; GKT 136901; GKT 137831; HYDROGEN PEROXIDE; OXALYL HYDRAZIDE DERIVATIVE; OXIDOREDUCTASE INHIBITOR; OXINDOLE; OXYGEN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4 INHIBITOR; S 17834; UNCLASSIFIED DRUG; NOX4 PROTEIN, HUMAN; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE;

ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CELL DEATH; CELL MIGRATION; CELL PROLIFERATION; DIABETIC NEPHROPATHY; ENDOTHELIAL DYSFUNCTION; ENDOTHELIUM CELL; ENDOTHELIUM INJURY; GENE; HEART VENTRICLE HYPERTROPHY; HUMAN; HYPERTENSION; MOLECULAR PATHOLOGY; NEOPLASM; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4 GENE; REVIEW; CHEMISTRY; GENETICS; METABOLISM; NEOVASCULARIZATION (PATHOLOGY); OXIDATION REDUCTION REACTION; PHYSIOLOGY; VASCULARIZATION;

CARDIOVASCULAR DISEASES; HUMANS; NADPH OXIDASE; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; OXIDATION-REDUCTION; REACTIVE OXYGEN SPECIES;

EID: 84945931340     PISSN: 1061186X     EISSN: 10292330     Source Type: Journal    
DOI: 10.3109/1061186X.2015.1036276     Document Type: Review

References (147)

1. Shiose A, Kuroda J, Tsuruya K, et al. A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem 2001;276:1417-23.
2. Geiszt M, Kopp JB, Várnai P, et al. Identification of renox, an NAD (P) H oxidase in kidney. Proc Natl Acad Sci USA 2000;97:8010-14.
3. Block K, Gorin Y, Abboud HE. Subcellular localization of Nox4 and regulation in diabetes. Proc Natl Acad Sci USA 2009;106:14385-90.
4. Altenhöfer S, Kleikers PW, Radermacher KA, et al. The NOX toolbox: validating the role of NADPH oxidases in physiology and disease. Cell Mol Life Sci 2012;69:2327-43.
5. Goyal P, Weissmann N, Rose F, et al. Identification of novel Nox4 splice variants with impact on ROS levels in A549 cells. Biochem Biophys Res Commun 2005;329:32-9.
6. Anilkumar N, San Jose G, Sawyer I, et al. A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and involved in redox signaling in vascular cells. Arterioscler Thromb Vasc Biol 2013;33:e104-12.
7. Mittal M, Roth M, König P, et al. Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 2007;101:258-67.
8. Pendyala S, Moitra J, Kalari S, et al. Nrf2 regulates hyperoxia-induced Nox4 expression in human lung endothelium: identification of functional antioxidant response elements on the Nox4 promoter. Free Radic Biol Med 2011;50:1749-59.
9. Sedeek M, Callera G, Montezano A, et al. Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol Renal Physiol 2010;299:F1348-58.
10. Cunningham KS, Gotlieb AI. The role of shear stress in the pathogenesis of atherosclerosis. Lab Investig 2004;85:9-23.
11. Goettsch C, Goettsch W, Arsov A, et al. Long-term cyclic strain downregulates endothelial Nox4. Antioxid Redox signal 2009;11:2385-97.
12. Ago T, Kuroda J, Pain J, et al. Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ Res 2010;106:1253-64.
13. Zhang L, Sheppard OR, Shah AM, et al. Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F. Free Radic Biol Med 2008;45:679-85.
14. Diebold I, Petry A, Hess J, et al. The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1. Mol Biol Cell 2010;21:2087-96.
15. Lu X, Murphy TC, Nanes MS, et al. PPARγ regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-κB. Am J Physiol Lung Cell Mol Physiol 2010;299:L559-66.
16. Goettsch C, Goettsch W, Brux M, et al. Arterial flow reduces oxidative stress via an antioxidant response element and Oct-1 binding site within the NADPH oxidase 4 promoter in endothelial cells. Basic Res Cardiol 2011;106:551-61.
17. Katsuyama M, Hirai H, Iwata K, et al. Sp3 transcription factor is crucial for transcriptional activation of the human NOX4 gene. FEBS J 2011;278:964-72.
18. Siuda D, Zechner U, El Hajj N, et al. Transcriptional regulation of Nox4 by histone deacetylases in human endothelial cells. Basic Res Cardiol 2012;107:1-12.
19. Manea A, Tanase LI, Raicu M, et al. Jak/STAT signaling pathway regulates nox1 and nox4-based NADPH oxidase in human aortic smooth muscle cells. Arterioscler Thromb Vasc Biol 2010;30:105-12.
20. Wingler K, Wunsch S, Kreutz R, et al. 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 2001;31:1456-64.
21. Kuroda J, Nakagawa K, Yamasaki T, et al. The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells. Genes Cells 2005;10:1139-51.
22. Jackson HM, Kawahara T, Nisimoto Y, et al. Nox4 B-loop creates an interface between the transmembrane and dehydrogenase domains. J Biol Chem 2010;285:10281-90.
23. Takac I, Schroder K, Zhang L, et al. The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem 2011;286:13304-13.
24. Nisimoto Y, Diebold BA, Cosentino-Gomes D, et al. Nox4: a hydrogen peroxide-generating oxygen sensor. Biochemistry 2014;53:5111-20.
25. 558 in phagocytes - differential sensitivity to calcium and phosphorylation events. Biochim Biophys Acta Biomembranes 2011;1808:78-90.
26. Li XJ, Grunwald D, Mathieu J, et al. Crucial role of two potential cytosolic regions of Nox2, 191TSSTKTIRRS200 and 484DESQANHFAVHHDEEKD500, on NADPH oxidase activation. J Biol Chem 2005;280:14962-73.
27. Varga ZV, Kupai K, Szu{combining double acute accent}cs G, et al. MicroRNA-25-dependent upregulation of NADPH oxidase 4 (NOX4) mediates hypercholesterolemia-induced oxidative/nitrative stress and subsequent dysfunction in the heart. J Mol Cell Cardiol 2013;62:111-21.
28. Gordillo GM, Biswas A, Khanna S, et al. Dicer knockdown inhibits endothelial cell tumor growth via microRNA 21a-3p targeting of Nox-4. J Biol Chem 2014;289:9027-38.
29. Serrander L, Cartier L, Bedard K, et al. NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J 2007;406:105-14.
30. Lyle AN, Deshpande NN, Taniyama Y, et al. Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res 2009;105:249-59.
31. Janiszewski M, Lopes LR, Carmo AO, et al. Regulation of NAD(P)H oxidase by associated protein disulfide isomerase in vascular smooth muscle cells. J Biol Chem 2005;280:40813-19.
32. Laurindo FR, Fernandes DC, Amanso AM, et al. Novel role of protein disulfide isomerase in the regulation of NADPH oxidase activity: pathophysiological implications in vascular diseases. Antioxid Redox Signal 2008;10:1101-14.
33. Datla SR, Dikalova A, Lyle AN, et al. Poldip2, a nox4 interacting protein, regulates vascular smooth muscle cell migration via rhoa-dependent focal adhesion turnover. Circulation 2010;122:A18285.
34. Datla SR, McGrail DJ, Vukelic S, et al. Poldip2 controls vascular smooth muscle cell migration by regulating focal adhesion turnover and force polarization. Am J Physiol Heart Circ Physiol 2014;30:H945-57.
35. Diaz B, Shani G, Pass I, et al. Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation. Sci Signal 2009;2:ra53.
36. Lorenzo AFG, Bocanegra V, Benardon ME, et al. Hsp70 regulation on Nox4/p22phox and cytoskeletal integrity as an effect of losartan in vascular smooth muscle cells. Cell Stress Chaperones 2014;19:115-34.
37. Desai LP, Zhou Y, Estrada AV, et al. Negative regulation of NADPH oxidase-4 by hydrogen peroxide inducible clone-5. J Biol Chem 2014;289:18270-8.
38. Kuroda J, Nakagawa K, Yamasaki T, et al. The superoxide-producing NAD (P) H oxidase Nox4 in the nucleus of human vascular endothelial cells. Genes Cells 2005;10:1139-51.
39. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 2004;4:181-9.
40. Cai H, Griendling KK, Harrison DG. The vascular NAD (P) H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 2003;24:471-8.
41. Martyn KD, Frederick LM, von Loehneysen K, et al. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal 2006;18:69-82.
42. Ambasta RK, Kumar P, Griendling KK, et al. Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase. J Biol Chem 2004;279:45935-41.
43. Schröder K, Zhang M, Benkhoff S, et al. Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res 2012;110:1217-25.
44. von Löhneysen K, Noack D, Hayes P, et al. Constitutive NADPH oxidase 4 activity resides in the composition of the B-loop and the penultimate C terminus. J Biol Chem 2012;287:8737-45.
45. Zeng W, Qiu G, Zhou H, et al. Community structure and dynamics of the free and attached microorganisms during moderately thermophilic bioleaching of chalcopyrite concentrate. Biores Technol 2010;101:7068-75.
46. Clempus RE, Sorescu D, Dikalova AE, et al. Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 2007;27:42-8.
47. Dikalov SI, Dikalova AE, Bikineyeva AT, et al. Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production. Free Radic Biol Med 2008;45:1340-51.
48. Rodino-Janeiro BK, Paradela-Dobarro B, Castineiras-Landeira MI, et al. Current status of NADPH oxidase research in cardiovascular pharmacology. Vasc Health Risk Manag 2013;9:401-28.
49. Lassegue B, San Martin A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 2012;110:1364-90.
50. Ateghang B. Regulation of cardiotrophin-1 expression in mouse embryonic stem cells by HIF-1 and intracellular reactive oxygen species. J Cell Sci 2006;119:1043-52.
51. Petry A, Djordjevic T, Weitnauer M, et al. NOX2 and NOX4 mediate proliferative response in endothelial cells. Antioxid Redox Signal 2006;8:1473-84.
52. Sturrock A, Cahill B, Norman K, et al. Transforming growth factor-β1 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 2006;290:L661-73.
53. Li S, Tabar SS, Malec V, et al. NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts. Antioxid Redox Signal 2008;10:1687-98.
54. Mofarrahi M, Brandes RP, Gorlach A, et al. Regulation of proliferation of skeletal muscle precursor cells by NADPH oxidase. Antioxid Redox Signal 2008;10:559-74.
55. Schroder K, Wandzioch K, Helmcke I, et al. Nox4 acts as a switch between differentiation and proliferation in preadipocytes. Arterioscler Thromb Vasc Biol 2008;29:239-45.
56. Shono T, Yokoyama N, Uesaka T, et al. Enhanced expression of NADPH oxidase Nox4 in human gliomas and its roles in cell proliferation and survival. Int J Cancer 2008;123:787-92.
57. Goettsch C, Goettsch W, Muller G, et al. Nox4 overexpression activates reactive oxygen species and p38 MAPK in human endothelial cells. Biochem Biophys Res Commun 2009;380:355-60.
58. Ismail S, Sturrock A, Wu P, et al. NOX4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-β1 and insulin-like growth factor binding protein-3. Am J Physiol Lung Cell Mol Physiol 2009;296:L489-99.
59. Lener B, Kozieł R, Pircher H, et al. The NADPH oxidase Nox4 restricts the replicative lifespan of human endothelial cells. Biochem J 2009;423:363-74.
60. Peshavariya H, Dusting GJ, Jiang F, et al. NADPH oxidase isoform selective regulation of endothelial cell proliferation and survival. Naunyn-Schmiedebergs Arch Pharmacol 2009;380:193-204.
61. Green DE, Murphy TC, Kang B-Y, et al. The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol 2012;47:718-26.
62. Przybylska D, Mosieniak G. The role of NADPH oxidase NOX4 in regulation of proliferation, senescence and differentiation of the cells. Postepy Biochem 2013;60:69-76.
63. Crosas-Molist E, Bertran E, Sancho P, et al. The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression. Free Radic Biol Med 2014;69:338-47.
64. Zhang C, Lan T, Hou J, et al. NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling. Oncotarget 2014;5:4392-405.
65. Jaulmes A, Sansilvestri-Morel P, Rolland-Valognes G, et al. Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells. Thrombosis Res 2009;124:439-46.
66. Schröder K, Wandzioch K, Helmcke I, et al. Nox4 acts as a switch between differentiation and proliferation in preadipocytes. Arterioscler Thromb Vasc Biol 2009;29:239-45.
67. Meng D, Lv D-D, Fang J. Insulin-like growth factor-I induces reactive oxygen species production and cell migration through Nox4 and Rac1 in vascular smooth muscle cells. Cardiovasc Res 2008;80:299-308.
68. Pendyala S, Gorshkova IA, Usatyuk PV, et al. Role of Nox4 and Nox2 in hyperoxia-induced reactive oxygen species generation and migration of human lung endothelial cells. Antioxid Redox Signal 2009;11:747-64.
69. Mondol AS, Tonks NK, Kamata T. Nox4 redox regulation of PTP1B contributes to the proliferation and migration of glioblastoma cells by modulating tyrosine phosphorylation of coronin-1C. Free Radic Biol Med 2014;67:285-91.
70. Tobar N, Guerrero J, Smith PC, et al. NOX4-dependent ROS production by stromal mammary cells modulates epithelial MCF-7 cell migration. Br J Cancer 2010;103:1040-7.
71. Boudreau HE, Korzeniowska A, Leto T. TGF-beta signaling regulates NADPH oxidase 4 (Nox4) - dependent oxidative stress and migration of human breast epithelial cells. FASEB J 2011;25:121.3.
72. Boudreau HE, Casterline BW, Rada B, et al. Nox4 involvement in TGF-beta and SMAD3-driven induction of the epithelial-to-mesenchymal transition and migration of breast epithelial cells. Free Radic Biol Med 2012;53:1489-99.
73. Haurani MJ, Cifuentes ME, Shepard AD, et al. Nox4 oxidase overexpression specifically decreases endogenous Nox4 mRNA and inhibits angiotensin II - induced adventitial myofibroblast migration. Hypertension 2008;52:143-9.
74. Montezano A, Burger D, Ceravolo G, et al. Novel Nox homologues in the vasculature: focusing on Nox4 and Nox5. Clin Sci 2011;120:131-41.
75. Hurd TR, DeGennaro M, Lehmann R. Redox regulation of cell migration and adhesion. Trends Cell Biol 2012;22:107-15.
76. Pedruzzi E, Guichard C, Ollivier V, et al. NAD (P) H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol 2004;24:10703-17.
77. Vaquero EC, Edderkaoui M, Pandol SJ, et al. Reactive oxygen species produced by NAD (P) H oxidase inhibit apoptosis in pancreatic cancer cells. J Biol Chem 2004;279:34643-54.
78. McKallip RJ, Jia W, Schlomer J, et al. Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 2006;70:897-908.
79. Kwon DS, Kwon CH, Kim JH, et al. Signal transduction of MEK/ERK and PI3K/Akt activation by hypoxia/reoxygenation in renal epithelial cells. Eur J Cell Biol 2006;85:1189-99.
80. Choi K, Han Y-H, Choi C. N-Acetyl cysteine and caffeic acid phenethyl ester sensitize astrocytoma cells to Fas-mediated cell death in a redox-dependent manner. Cancer Lett 2007;257:79-86.
81. Sancho P, Mainez J, Crosas-Molist E, et al. NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS One 2012;7:e45285.
82. Carmona-Cuenca I, Roncero C, Sancho P, et al. Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity. J Hepatol 2008;49:965-76.
83. Basuroy S, Bhattacharya S, Leffler CW, et al. Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-α in cerebral vascular endothelial cells. Am J Physiol Cell Physiol 2009;296:C422-32.
84. Caja L, Sancho P, Bertran E, et al. Overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGFβ-induced cell death through impairing up-regulation of the NADPH oxidase NOX4. Cancer Res 2009;69:7595-602.
85. Simon F, Fernandez R. Early lipopolysaccharide-induced reactive oxygen species production evokes necrotic cell death in human umbilical vein endothelial cells. J Hypertens 2009;27:1202-16.
86. Vanden Berghe T, Declercq W, Vandenabeele P. (Nox1) NADPH oxidases: new players in TNF-induced necrotic cell death. Mol Cell 2007;26:769-71.
87. Morgan MJ, Liu Z-g. Reactive oxygen species in TNFα-induced signaling and cell death. Mol Cells 2010;30:1-12.
88. Morgan MJ, Kim Y-S, Liu Z-g. TNFα and reactive oxygen species in necrotic cell death. Cell Res 2008;18:343-9.
89. Reinehr R, Becker S, Eberle A, et al. Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J Biol Chem 2005;280:27179-94.
90. Xu Y, Ruan S, Wu X, et al. Autophagy and apoptosis in tubular cells following unilateral ureteral obstruction are associated with mitochondrial oxidative stress. Int J Mol Med 2013;31:628-36.
91. Wang J, Yi J. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol Ther 2008;7:1875-84.
92. Kuroda J, Ago T, Matsushima S, et al. NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci USA 2010;107:15565-70.
93. Cross A, Henderson L, Jones O, et al. Involvement of an NAD (P) H oxidase as a pO2 sensor protein in the rat carotid body. Biochem J 1990;272:743-7.
94. Shiose A, Kuroda J, Tsuruya K, et al. A novel superoxide-producing NAD (P) H oxidase in kidney. J Biol Chem 2001;276:1417-23.
95. Diebold I, Flügel D, Becht S, et al. The hypoxia-inducible factor- 2α is stabilized by oxidative stress involving NOX4. Antioxid Redox Signal 2010;13:425-36.
96. Lee Y-M, Kim B-J, Chun Y-S, et al. NOX4 as an oxygen sensor to regulate TASK-1 activity. Cell Signal 2006;18:499-507.
97. Tam NN, Leav I, Ho SM. Sex hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the noble rat. Am J Pathol 2007;171:1334-41.
98. Gregg JL, Turner 2nd RM, Chang G, et al. NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2alpha. Cancer Res 2014;74:3501-11.
99. Crosas-Molist E, Bertran E, Sancho P, et al. The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression. Free Radic Biol Med 2014;69:338-47.
100. Shono T, Yokoyama N, Uesaka T, et al. Enhanced expression of NADPH oxidase Nox4 in human gliomas and its roles in cell proliferation and survival. Int J Cancer 2008;123:787-92.
101. Zhang C, Lan T, Hou J, et al. NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling. Oncotarget 2014;5:4392-405.
102. Zhang B, Liu Z, Hu X. Inhibiting cancer metastasis via targeting NAPDH oxidase 4. Biochem Pharmacol 2013;86:253-66.
103. Fitzgerald JP, Nayak B, Shanmugasundaram K, et al. Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8-production. PLoS One 2012;7:e30712.
104. Kim EY, Seo JM, Kim C, et al. BLT2 promotes the invasion and metastasis of aggressive bladder cancer cells through a reactive oxygen species-linked pathway. Free Radic Biol Med 2010;49:1072-81.
105. Ogrunc M, Di Micco R, Liontos M, et al. Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation. Cell Death Differ 2014;21:998-1012.
106. Mochizuki T, Furuta S, Mitsushita J, et al. Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signalregulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Oncogene 2006;25:3699-707.
107. Boudreau HE, Casterline BW, Rada B, et al. Nox4 involvement in TGF-beta and SMAD3-driven induction of the epithelial-tomesenchymal transition and migration of breast epithelial cells. Free Radic Biol Med 2012;53:1489-99.
108. Graham KA, Kulawiec M, Owens KM, et al. NADPH oxidase 4 is an oncoprotein localized to mitochondria. Cancer Biol Ther 2010;10:223-31.
109. Weyemi U, Lagente-Chevallier O, Boufraqech M, et al. ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence. Oncogene 2012;31:1117-29.
110. Ahmad M, Kelly MR, Zhao X, et al. Roles for Nox4 in the contractile response of bovine pulmonary arteries to hypoxia. Am J Physiol Heart Circ Physiol 2010;298:H1879-88.
111. Folkman J, Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002;29:15-18.
112. Maraldi T, Prata C, Caliceti C, et al. VEGF-induced ROS generation from NAD(P)H oxidases protects human leukemic cells from apoptosis. Int J Oncol 2010;36:1581-9.
113. Andreani A, Granaiola M, Locatelli A, et al. Cytotoxic activities of substituted 3-( 3, 4,5-trimethoxybenzylidene)-1,3-dihydroindol-2-ones and studies on their mechanisms of action. Eur J Med Chem 2013;64:603-12.
114. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. Clin Chem 2013;59:168-79.
115. Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer 2006;6:449-58.
116. Tobar N, Guerrero J, Smith PC, et al. NOX4-dependent ROS production by stromal mammary cells modulates epithelial MCF-7 cell migration. Br J Cancer 2010;103:1040-7.
117. Hsieh CH, Chang HT, Shen WC, et al. Imaging the impact of Nox4 in cycling hypoxia-mediated U87 glioblastoma invasion and infiltration. Mol Imaging Biol 2012;14:489-99.
118. Seo JM, Park S, Kim JH. Leukotriene B4 receptor-2 promotes invasiveness and metastasis of ovarian cancer cells through signal transducer and activator of transcription 3 (STAT3)-dependent upregulation of matrix metalloproteinase 2. J Biol Chem 2012;287:13840-9.
119. Hsieh CH, Shyu WC, Chiang CY, et al. NADPH oxidase subunit 4-mediated reactive oxygen species contribute to cycling hypoxiapromoted tumor progression in glioblastoma multiforme. PLoS One 2011;6:e23945.
120. Chang G, Chen L, Lin HM, et al. Nox4 inhibition enhances the cytotoxicity of cisplatin in human renal cancer cells. J Exp Ther Oncol 2012;10:9-18.
121. Holley AK, Xu Y, Noel T, et al. Manganese superoxide dismutasemediated inside-out signaling in HaCaT human keratinocytes and SKH-1 mouse skin. Antioxid Redox Signal 2014;20:2347-60.
122. Drummond GR, Selemidis S, Griendling KK, et al. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 2011;10:453-71.
123. Breton-Romero R, Gonzalez de Orduna C, Romero N, et al. Critical role of hydrogen peroxide signaling in the sequential activation of p38 MAPK and eNOS in laminar shear stress. Free Radic Biol Med 2012;52:1093-100.
124. Bretón-Romero R, Lamas S. Hydrogen peroxide signaling in vascular endothelial cells. Redox Biol 2014;2:529-34.
125. Liochev SI. Free radical paradoxes. Free Radic Biol Med 2013;65:232-3.
126. Thomas SR, Chen K, Keaney JF. Hydrogen peroxide activates endothelial nitric-oxide synthase through coordinated phosphorylation and dephosphorylation via a phosphoinositide 3-kinase-dependent signaling pathway. J Biol Chem 2002;277:6017-24.
127. Lee CF, Qiao M, Schröder K, et al. Nox4 is a novel inducible source of reactive oxygen species in monocytes and macrophages and mediates oxidized low density lipoprotein-induced macrophage death. Circ Res 2010;106:1489-97.
128. Lassègue B, San Martín A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 2012;110:1364-90.
129. Runge MS, Vendrov AE, Madamanchi NR. Nox4 NADPH oxidase-dependent mitochondrial oxidative stress promotes cardiovascular disease in aging. FASEB J 2013;27:1194.13.
130. Khandelwal AR, Chen L, Qin Z, et al. Role of Nox4 in modulating atherosclerosis in diabetes. FASEB J 2013;27:869.2.
131. Paravicini TM, Chrissobolis S, Drummond GR, et al. Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke 2004;35:584-9.
132. Ray R, Murdoch CE, Wang M, et al. Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo. Arterioscler Thromb Vasc Biol 2011;31:1368-76.
133. Cowley AW, Yang C, Kurth T, et al. Protective effect of Nox4 in salt-induced hypertension in dahl salt-induced rats. Hypertension 2013;62:A78.
134. Goncharov D, Ziai H, Ihida-Stansbury K, et al. Nox4 regulates Mtorc2-Akt signaling and vascular smooth muscle cell remodeling in pulmonary hypertension. Am J Respir Crit Care Med 2014;189:A3632.
135. Kuroda J, Ago T, Matsushima S, et al. NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci 2010;107:15565-70.
136. Ago T, Matsushima S, Kuroda J, et al. The NADPH oxidase Nox4 and aging in the heart. Aging (Albany NY) 2010;2:1012-16.
137. Seddon M, Looi YH, Shah AM. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 2007;93:903-7.
138. Zhang M, Perino A, Ghigo A, et al. NADPH oxidases in heart failure: poachers or gamekeepers? Antioxid Redox Signal 2013;18:1024-41.
139. Zhang J, Youn JY, Kim AY, et al. NOX4-dependent hydrogen peroxide overproduction in human atrial fibrillation and HL-1 atrial cells: relationship to hypertension. Front Physiol 2012;3:140. DOI: http://dx.doi.org/10.3389/fphys.2012.00140.
140. Borbely G, Szabadkai I, Horvath Z, et al. Small-molecule inhibitors of NADPH oxidase 4. J Med Chem 2010;53:6758-62.
141. Bhandarkar SS, Jaconi M, Fried LE, et al. Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice. J Clin Invest 2009;119:2359-65.
142. Ding Y, Chen ZJ, Liu S, et al. Inhibition of Nox-4 activity by plumbagin, a plant-derived bioactive naphthoquinone. J Pharm Pharmacol 2005;57:111-16.
143. Bayat H, Schroder K, Pimentel DR, et al. Activation of thromboxane receptor modulates interleukin-1beta-induced monocyte adhesion - a novel role of Nox1. Free Radic Biol Med 2012;52:1760-6.
144. Green DE, Murphy TC, Kang BY, et al. The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol 2012;47:718-26.
145. Cayatte AJ, Rupin A, Oliver-Krasinski J, et al. S17834, a new inhibitor of cell adhesion and atherosclerosis that targets NADPH oxidase. Arterioscler Thromb Vasc Biol 2001;21:1577-84.
146. Cai WX, Liang L, Wang L, et al. Inhibition of Notch signaling leads to increased intracellular ROS by up-regulating Nox4 expression in primary HUVECs. Cell Immunol 2014;287:129-35.
147. Pagano PJ. Strategies aimed at Nox4 oxidase inhibition employing peptides from Nox4 B-loop and C-terminus and p22 phox N-terminus: an elusive target. Int J Hypertens 2013;2013:1-9. DOI: http://dx.doi.org/10.1155/2013/842827.