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NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology

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Abstract

Reactive oxygen species (ROS) are essential mediators of normal cell physiology. However, in the last few decades, it has become evident that ROS overproduction and/or alterations of the antioxidant system associated with inflammation and metabolic dysfunction are key pathological triggers of cardiovascular disorders. NADPH oxidases (Nox) represent a class of hetero-oligomeric enzymes whose primary function is the generation of ROS. In the vasculature, Nox-derived ROS contribute to the maintenance of vascular tone and regulate important processes such as cell growth, proliferation, differentiation, apoptosis, cytoskeletal organization, and cell migration. Under pathological conditions, excessive Nox-dependent ROS formation, which is generally associated with the up-regulation of different Nox subtypes, induces dysregulation of the redox control systems and promotes oxidative injury of the cardiovascular cells. The molecular mechanism of Nox-derived ROS generation and the means by which this class of molecule contributes to vascular damage remain debatable issues. This review focuses on the processes of ROS formation, molecular targets, and neutralization in the vasculature and provides an overview of the novel concepts regarding Nox functions, expression, and regulation in vascular health and disease. Because Nox enzymes are the most important sources of ROS in the vasculature, therapeutic perspectives to counteract Nox-dependent oxidative stress in the cardiovascular system are discussed.

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References

  • Ago T, Kuroda J, Pain J, Fu C, Li H, Sadoshima J (2010) Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ Res 106:1253–1264

    Article  PubMed  CAS  Google Scholar 

  • Anrather J, Rackham G, Iadecola C (2006) NF-kappaB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. J Biol Chem 281:5657–5667

    Article  PubMed  CAS  Google Scholar 

  • Arora S, Vaishya R, Dabla PK, Singh B (2010) NAD(P)H oxidases in coronary artery disease. Adv Clin Chem 50:65–86

    Article  PubMed  CAS  Google Scholar 

  • Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • BelAiba RS, Djordjevic T, Petry A, Diemer K, Bonello S, Banfi B, Hess J, Pogrebniak A, Bickel C, Görlach A (2007) NOX5 variants are functionally active in endothelial cells. Free Radic Biol Med 42:446–459

    Article  PubMed  CAS  Google Scholar 

  • Belia S, Santilli F, Beccafico S, De Feudis L, Morabito C, Davi G, Fanò G, Mariggiò MA (2009) Oxidative-induced membrane damage in diabetes lymphocytes: effects on intracellular Ca(2+) homeostasis. Free Radic Res 43:138–148

    Article  PubMed  CAS  Google Scholar 

  • Block K, Eid A, Griendling KK, Lee DY, Wittrant Y, Gorin Y (2008) Nox4 NAD(P)H oxidase mediates Src-dependent tyrosine phosphorylation of PDK-1 in response to angiotensin II: role in mesangial cell hypertrophy and fibronectin expression. J Biol Chem 283:24061–24076

    Article  PubMed  CAS  Google Scholar 

  • Brewer AC, Sparks EC, Shah AM (2006) Transcriptional regulation of the NADPH oxidase isoform, Nox1, in colon epithelial cells: role of GATA-binding factor(s). Free Radic Biol Med 40:260–274

    Article  PubMed  CAS  Google Scholar 

  • Briones AM, Touyz RM (2010) Oxidative stress and hypertension: current concepts. Curr Hypertens Rep 12:135–142

    Article  PubMed  CAS  Google Scholar 

  • Castor LR, Locatelli KA, Ximenes VF (2010) Pro-oxidant activity of apocynin radical. Free Radic Biol Med 48:1636–1643

    Article  PubMed  CAS  Google Scholar 

  • Ceolotto G, Gallo A, Papparella I, Franco L, Murphy E, Iori E, Pagnin E, Fadini GP, Albiero M, Semplicini A, Avogaro A (2007) Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism. Arterioscler Thromb Vasc Biol 27:2627–2633

    Article  PubMed  CAS  Google Scholar 

  • Cevik MO, Katsuyama M, Kanda S, Kaneko T, Iwata K, Ibi M, Matsuno K, Kakehi T, Cui W, Sasaki M, Yabe-Nishimura C (2008) The AP-1 site is essential for the promoter activity of NOX1/NADPH oxidase, a vascular superoxide-producing enzyme: possible involvement of the ERK1/2-JunB pathway. Biochem Biophys Res Commun 374:351–355

    Article  PubMed  CAS  Google Scholar 

  • Chen Z, Keaney JF Jr, Schulz E, Levison B, Shan L, Sakuma M, Zhang X, Shi C, Hazen SL, Simon DI (2004) Decreased neointimal formation in Nox2-deficient mice reveals a direct role for NADPH oxidase in the response to arterial injury. Proc Natl Acad Sci USA 101:13014–13019

    Article  PubMed  CAS  Google Scholar 

  • Cohen RA, Tong X (2010) Vascular oxidative stress: the common link in hypertensive and diabetic vascular disease. J Cardiovasc Pharmacol 55:308–316

    Article  PubMed  CAS  Google Scholar 

  • Csányi G, Taylor WR, Pagano PJ (2009) NOX and inflammation in the vascular adventitia. Free Radic Biol Med 47:1254–1266

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A (2006) Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med 10:389–406

    Article  PubMed  CAS  Google Scholar 

  • De Ciuceis C, Amiri F, Iglarz M, Cohn JS, Touyz RM, Schiffrin EL (2007) Synergistic vascular protective effects of combined low doses of PPARalpha and PPARgamma activators in angiotensin II-induced hypertension in rats. Br J Pharmacol 151:45–53

    Article  PubMed  CAS  Google Scholar 

  • Diebold I, Petry A, Hess J, Görlach A (2010) The NADPH oxidase subunit NOX4 Is a new target gene of the hypoxia-inducible factor-1. Mol Biol Cell 10:2087–2096

    Article  CAS  Google Scholar 

  • Diep QN, Amiri F, Touyz RM, Cohn JS, Endemann D, Neves MF, Schiffrin EL (2002) PPARalpha activator effects on Ang II-induced vascular oxidative stress and inflammation. Hypertension 40:866–871

    Article  PubMed  CAS  Google Scholar 

  • Diep QN, Benkirane K, Amiri F, Cohn JS, Endemann D, Schiffrin EL (2004) PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats. J Mol Cell Cardiol 36:295–304

    Article  PubMed  CAS  Google Scholar 

  • Ding H, Hashem M, Triggle C (2007) Increased oxidative stress in the streptozotocin-induced diabetic apoE-deficient mouse: changes in expression of NADPH oxidase subunits and eNOS. Eur J Pharmacol 561:121–128

    Article  PubMed  CAS  Google Scholar 

  • Dobrian AD, Schriver SD, Khraibi AA, Prewitt RL (2004) Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. Hypertension 43:48–56

    Article  PubMed  CAS  Google Scholar 

  • Fearon IM, Faux SP (2009) Oxidative stress and cardiovascular disease: novel tools give (free) radical insight. J Mol Cell Cardiol 47:372–381

    Article  PubMed  CAS  Google Scholar 

  • Forman HJ, Maiorino M, Ursini F (2010) Signaling functions of reactive oxygen species. Biochemistry 49:835–842

    Article  PubMed  CAS  Google Scholar 

  • Förstermann U (2008) Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 5:338–349

    Article  PubMed  CAS  Google Scholar 

  • Fortuño A, Bidegain J, Robador PA, Hermida J, López-Sagaseta J, Beloqui O, Díez J, Zalba G (2009) Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension. Hypertension 54:744–750

    Article  PubMed  CAS  Google Scholar 

  • Fulton DJ (2009) Nox5 and the regulation of cellular function. Antioxid Redox Signal 11:2443–2452

    Article  PubMed  CAS  Google Scholar 

  • Gao L, Mann GE (2009) Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. Cardiovasc Res 82:9–20

    Article  PubMed  CAS  Google Scholar 

  • Gauss KA, Nelson-Overton LK, Siemsen DW, Gao Y, DeLeo FR, Quinn MT (2007) Role of NF-kappaB in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor-alpha. J Leukoc Biol 82:729–741

    Article  PubMed  CAS  Google Scholar 

  • Gavazzi G, Deffert C, Trocme C, Schäppi M, Herrmann FR, Krause KH (2007) NOX1 deficiency protects from aortic dissection in response to angiotensin II. Hypertension 50:189–196

    Article  PubMed  CAS  Google Scholar 

  • Genolet R, Wahli W, Michalik L (2004) PPARs as drug targets to modulate inflammatory responses? Curr Drug Targets Inflamm Allergy 3:361–375

    Article  PubMed  CAS  Google Scholar 

  • Gianni D, Bohl B, Courtneidge SA, Bokoch GM (2008) The involvement of the tyrosine kinase c-Src in the regulation of reactive oxygen species generation mediated by NADPH oxidase-1. Mol Biol Cell 19:2984–2994

    Article  PubMed  CAS  Google Scholar 

  • Go YM, Jones DP (2010) Redox control systems in the nucleus: mechanisms and functions. Antioxid Redox Signal 13:489–509

    Article  PubMed  CAS  Google Scholar 

  • Goyal P, Weissmann N, Grimminger F, Hegel C, Bader L, Rose F, Fink L, Ghofrani HA, Schermuly RT, Schmidt HH, Seeger W, Hänze J (2004) Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxia-inducible factor 1 via increase in reactive oxygen species. Free Radic Biol Med 36:1279–1288

    Article  PubMed  CAS  Google Scholar 

  • Katsuyama M, Fan C, Arakawa N, Nishinaka T, Miyagishi M, Taira K, Yabe-Nishimura C (2005) Essential role of ATF-1 in induction of NOX1, a catalytic subunit of NADPH oxidase: involvement of mitochondrial respiratory chain. Biochem J 386:255–261

    Article  PubMed  CAS  Google Scholar 

  • Harvey EJ, Ramji DP (2005) Interferon-gamma and atherosclerosis: pro- or anti-atherogenic? Cardiovasc Res 67:11–20

    Article  PubMed  CAS  Google Scholar 

  • Heistad DD, Wakisaka Y, Miller J, Chu Y, Pena-Silva R (2009) Novel aspects of oxidative stress in cardiovascular diseases. Circ J 73:201–207

    Article  PubMed  CAS  Google Scholar 

  • Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK (2004) Distinct subcellular localizations of Nox1 and Nox in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 24:677–683

    Article  PubMed  CAS  Google Scholar 

  • Hoyal CR, Gutierrez A, Young BM, Catz SD, Lin JH, Tsichlis PN, Babior BM (2003)Modulation of p47PHOX activity by site-specific phosphorylation: Akt-dependent activation of the NADPH oxidase.Proc Natl Acad Sci USA 100:5130–5135

    Article  PubMed  CAS  Google Scholar 

  • Huang W, Glass CK (2010) Nuclear receptors and inflammation control: molecular mechanisms and pathophysiological relevance. Arterioscler Thromb Vasc Biol 30:1542–1549

    Article  PubMed  CAS  Google Scholar 

  • Hultqvist M, Olsson LM, Gelderman KA, Holmdahl R (2009) The protective role of ROS in autoimmune disease. Trends Immunol 30:201–208

    Article  PubMed  CAS  Google Scholar 

  • Hwang J, Kleinhenz DJ, Rupnow HL, Campbell AG, Thulé PM, Sutliff RL, Hart CM (2007) The PPARgamma ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice. Vascul Pharmacol 46:456–462

    Article  PubMed  CAS  Google Scholar 

  • Janiszewski M, Lopes LR, Carmo AO, Pedro MA, Brandes RP, Santos CX, Laurindo FR (2005) Regulation of NAD(P)H oxidase by associated protein disulfide isomerase in vascular smooth muscle cells. J Biol Chem 280:40813–40819

    Article  PubMed  CAS  Google Scholar 

  • Jaquet V, Scapozza L, Clark RA, Krause KH, Lambeth JD (2009) Small-molecule NOX inhibitors: ROS-generating NADPH oxidases as therapeutic targets. Antioxid Redox Signal 11:2535–2552

    Article  PubMed  CAS  Google Scholar 

  • Jaulmes A, Sansilvestri-Morel P, Rolland-Valognes G, Bernhardt F, Gaertner R, Lockhart BP, Cordi A, Wierzbicki M, Rupin A, Verbeuren TJ (2009) Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells. Thromb Res 124:439–446

    Article  PubMed  CAS  Google Scholar 

  • Jay DB, Papaharalambus CA, Seidel-Rogol B, Dikalova AE, Lassègue B, Griendling KK (2008) Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells. Free Radic Biol Med 45:329–335

    Article  PubMed  CAS  Google Scholar 

  • Kakar R, Kautz B, Eklund EA (2005) JAK2 is necessary and sufficient for interferon-gamma-induced transcription of the gene encoding gp91PHOX. J Leukoc Biol 77:120–127

    PubMed  CAS  Google Scholar 

  • Kilpatrick LE, Sun S, Li H, Vary TC, Korchak HM (2010) Regulation of TNF-induced oxygen radical production in human neutrophils: role of delta-PKC. J Leukoc Biol 87:153–164

    Article  PubMed  CAS  Google Scholar 

  • Kim JS, Diebold BA, Babior BM, Knaus UG, Bokoch GM (2007) Regulation of Nox1 activity via protein kinase A-mediated phosphorylation of NoxA1 and 14-3-3 binding. J Biol Chem 282:34787–34800

    Article  PubMed  CAS  Google Scholar 

  • Kondo T, Hirose M, Kageyama K (2009) Roles of oxidative stress and redox regulation in atherosclerosis. J Atheroscler Thromb 16:532–538

    PubMed  CAS  Google Scholar 

  • Kuroda J, Sadoshima J (2010) NADPH oxidase and cardiac failure. J Cardiovasc Transl Res 3:314–320

    Article  PubMed  Google Scholar 

  • Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189

    Article  PubMed  CAS  Google Scholar 

  • Lambeth JD (2007) Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med 43:332–347

    Article  PubMed  CAS  Google Scholar 

  • Lambeth JD, Krause KH, Clark RA (2008) NOX enzymes as novel targets for drug development. Semin Immunopathol 30:339–363

    Article  PubMed  CAS  Google Scholar 

  • Lassègue B, Griendling KK (2002) Out phoxing the endothelium: what's left without p47?Circ Res 90:123–124

    PubMed  Google Scholar 

  • Lassègue B, Sorescu D, Szöcs K, Yin Q, Akers M, Zhang Y, Grant SL, Lambeth JD, Griendling KK (2001) Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res 88:888–894

    Article  PubMed  Google Scholar 

  • Lavrentyev EN, Malik KU (2009) High glucose-induced Nox1-derived superoxides downregulate PKC-betaII, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs. Am J Physiol Heart Circ Physiol 296:H106–H118

    Article  PubMed  CAS  Google Scholar 

  • Lee MY, Griendling KK (2008) Redox signaling, vascular function, and hypertension. Antioxid Redox Signal 10:1045–1059

    Article  PubMed  CAS  Google Scholar 

  • Lee JG, Lim EJ, Park DW, Lee SH, Kim JR, Baek SH (2008) A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation. Cell Signal 20:2266–2275

    Article  PubMed  CAS  Google Scholar 

  • Lee MY, San Martin A, Mehta PK, Dikalova AE, Garrido AM, Datla SR, Lyons E, Krause KH, Banfi B, Lambeth JD, Lassègue B, Griendling KK (2009) Mechanisms of vascular smooth muscle NADPH oxidase 1 (Nox1) contribution to injury-induced neointimal formation. Arterioscler Thromb Vasc Biol 29:480–487

    Article  PubMed  CAS  Google Scholar 

  • Li JM, Shah AM (2003) Mechanism of endothelial cell NADPH oxidase activation by angiotensin II. Role of the p47phox subunit.J Biol Chem 278:12094–12100

    Article  PubMed  CAS  Google Scholar 

  • Liu H, Colavitti R, Rovira II, Finkel T (2005) Redox-dependent transcriptional regulation. Circ Res 97:967–974

    Article  PubMed  CAS  Google Scholar 

  • Lyle AN, Deshpande NN, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P, Papaharalambus C, Lassègue B, Griendling KK (2009) Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res 105:249–259

    Article  PubMed  CAS  Google Scholar 

  • Maitra U, Singh N, Gan L, Ringwood L, Li L (2009) IRAK-1 contributes to lipopolysaccharide-induced reactive oxygen species generation in macrophages by inducing NOX-1 transcription and Rac1 activation and suppressing the expression of antioxidative enzymes. J Biol Chem 284:35403–35411

    Article  PubMed  CAS  Google Scholar 

  • Maloney E, Sweet IR, Hockenbery DM, Pham M, Rizzo NO, Tateya S, Handa P, Schwartz MW, Kim F (2009) Activation of NF-kappaB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation. Arterioscler Thromb Vasc Biol 29:1370–1375

    Article  PubMed  CAS  Google Scholar 

  • Manea A, Constantinescu E, Popov D, Raicu M (2004) Changes in oxidative balance in rat pericytes exposed to diabetic conditions. J Cell Mol Med 8:117–126

    Article  PubMed  CAS  Google Scholar 

  • Manea A, Raicu M, Simionescu M (2005) Expression of functionally phagocyte-type NAD(P)H oxidase in pericytes: effect of angiotensin II and high glucose. Biol Cell 97:723–734

    Article  PubMed  CAS  Google Scholar 

  • Manea A, Manea SA, Gafencu AV, Raicu M (2007) Regulation of NADPH oxidase subunit p22(phox) by NF-kB in human aortic smooth muscle cells. Arch Physiol Biochem 113:163–172

    Article  PubMed  CAS  Google Scholar 

  • Manea A, Manea SA, Gafencu AV, Raicu M, Simionescu M (2008) AP-1-dependent transcriptional regulation of NADPH oxidase in human aortic smooth muscle cells: role of p22phox subunit. Arterioscler Thromb Vasc Biol 28:878–885

    Article  PubMed  CAS  Google Scholar 

  • Manea A, Tanase LI, Raicu M, Simionescu M (2010a) JAK/STAT signaling pathway regulates Nox1 and Nox4-based NADPH oxidase in human aortic smooth muscle cells. Arterioscler Thromb Vasc Biol 30:105–112

    Article  PubMed  CAS  Google Scholar 

  • Manea A, Tanase LI, Raicu M, Simionescu M (2010b) Transcriptional regulation of NADPH oxidase isoforms, Nox1 and Nox4, by nuclear factor-kB in human aortic smooth muscle cells. Biochem Biophys Res Commun 396:901–907

    Article  PubMed  CAS  Google Scholar 

  • Manea SA, Manea A, Heltianu C (2010c) Inhibition of JAK/STAT signaling pathway prevents high-glucose-induced increase in endothelin-1 synthesis in human endothelial cells. Cell Tissue Res 340:71–79

    Article  PubMed  CAS  Google Scholar 

  • Marrero MB (2005) Introduction to JAK/STAT signaling and the vasculature. Vascul Pharmacol 43:307–309

    Article  PubMed  CAS  Google Scholar 

  • Martinet W, Knaapen MW, De Meyer GR, Herman AG, Kockx MM (2001) Oxidative DNA damage and repair in experimental atherosclerosis are reversed by dietary lipid lowering. Circ Res 88:733–739

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Miller FJ Jr, Filali M, Huss GJ, Stanic B, Chamseddine A, Barna TJ, Lamb FS (2007) Cytokine activation of nuclear factor kappa B in vascular smooth muscle cells requires signaling endosomes containing Nox1 and ClC-3. Circ Res 101:663–671

    Article  PubMed  CAS  Google Scholar 

  • Miller JD, Chu Y, Brooks RM, Richenbacher WE, Peña-Silva R, Heistad DD (2008) Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol 52:843–850

    Article  PubMed  CAS  Google Scholar 

  • Miller JD, Peotta VA, Chu Y, Weiss RM, Zimmerman K, Brooks RM, Heistad DD (2010) MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure. Am J Physiol Heart Circ Physiol 298:1600–1607

    Article  CAS  Google Scholar 

  • Moe KT, Aulia S, Jiang F, Chua YL, Koh TH, Wong MC, Dusting GJ (2006) Differential upregulation of Nox homologues of NADPH oxidase by tumor necrosis factor-alpha in human aortic smooth muscle and embryonic kidney cells. J Cell Mol Med 10:231–239

    Article  PubMed  CAS  Google Scholar 

  • Montezano AC, Burger D, Paravicini TM, Chignalia AZ, Yusuf H, Almasri M, He Y, Callera GE, He G, Krause KH, Lambeth D, Quinn MT, Touyz RM (2010) Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (Nox5) regulation by angiotensin II and endothelin-1 is mediated via calcium/calmodulin-dependent, rac-1-independent pathways in human endothelial cells. Circ Res 106:1363–1373

    Article  PubMed  CAS  Google Scholar 

  • Ni W, Zhan Y, He H, Maynard E, Balschi JA, Oettgen P (2007) Ets-1 is a critical transcriptional regulator of reactive oxygen species and p47(phox) gene expression in response to angiotensin II. Circ Res 101:985–994

    Article  PubMed  CAS  Google Scholar 

  • Nishi K, Oda T, Takabuchi S, Oda S, Fukuda K, Adachi T, Semenza GL, Shingu K, Hirota K (2008) LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species-dependent manner. Antioxid Redox Signal 10:983–995

    Article  PubMed  CAS  Google Scholar 

  • Niu XL, Madamanchi NR, Vendrov AE, Tchivilev I, Rojas M, Madamanchi C, Brandes RP, Krause KH, Humphries J, Smith A, Burnand KG, Runge MS (2010) Nox activator 1: a potential target for modulation of vascular reactive oxygen species in atherosclerotic arteries. Circulation 121:549–559

    Article  PubMed  CAS  Google Scholar 

  • Olukman M, Orhan CE, Celenk FG, Ulker S (2010) Apocynin restores endothelial dysfunction in streptozotocin diabetic rats through regulation of nitric oxide synthase and NADPH oxidase expressions. J Diab Complications. doi:10.1016/j.jdiacomp.2010.02.001

    Google Scholar 

  • Oshikawa J, Urao N, Kim HW, Kaplan N, Razvi M, McKinney R, Poole LB, Fukai T, Ushio-Fukai M (2010) Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLoS ONE 5:e10189

    Article  PubMed  CAS  Google Scholar 

  • Papatheodorou L, Weiss N (2007) Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxid Redox Signal 9:1941–1958

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Popov D (2009) Vascular PTPs: current developments and challenges for exploitation in Type 2 diabetes-associated vascular dysfunction. Biochem Biophys Res Commun 389:1–4

    Article  PubMed  CAS  Google Scholar 

  • Rivera J, Sobey CG, Walduck AK, Drummond GR (2010) Nox isoforms in vascular pathophysiology: insights from transgenic and knockout mouse models. Redox Rep 15:50–63

    Article  PubMed  CAS  Google Scholar 

  • Roy S, Khanna S, Sen CK (2008) Redox regulation of the VEGF signaling path and tissue vascularization: hydrogen peroxide, the common link between physical exercise and cutaneous wound healing. Free Radic Biol Med 44:180–192

    Article  PubMed  CAS  Google Scholar 

  • Ryoo S, Lemmon CA, Soucy KG, Gupta G, White AR, Nyhan D, Shoukas A, Romer LH, Berkowitz DE (2006) Oxidized low-density lipoprotein-dependent endothelial arginase II activation contributes to impaired nitric oxide signaling. Circ Res 99:951–960

    Article  PubMed  CAS  Google Scholar 

  • Sádaba LM, Fernández-Robredo P, Rodríguez JA, García-Layana A (2008) Antioxidant effects of vitamins C and E, multivitamin-mineral complex and flavonoids in a model of retinal oxidative stress: the ApoE-deficient mouse. Exp Eye Res 86:470–479

    Article  PubMed  CAS  Google Scholar 

  • Schäppi MG, Jaquet V, Belli DC, Krause KH (2008) Hyperinflammation in chronic granulomatous disease and anti-inflammatory role of the phagocyte NADPH oxidase. Semin Immunopathol 30:255–271

    Article  PubMed  CAS  Google Scholar 

  • Schiffrin EL, Amiri F, Benkirane K, Iglarz M, Diep QN (2003) Peroxisome proliferator-activated receptors: vascular and cardiac effects in hypertension. Hypertension 42:664–668

    Article  PubMed  CAS  Google Scholar 

  • Schrader M, Fahimi HD (2006) Peroxisomes and oxidative stress. Biochim Biophys Acta 1763:1755–1766

    Article  PubMed  CAS  Google Scholar 

  • Sedeek M, Hébert RL, Kennedy CR, Burns KD, Touyz RM (2009) Molecular mechanisms of hypertension: role of Nox family NADPH oxidases. Curr Opin Nephrol Hypertens 18:122–127

    Article  PubMed  CAS  Google Scholar 

  • Seitz PM, Cooper R, Gatto GJ Jr, Ramon F, Sweitzer TD, Johns DG, Davenport EA, Ames RS, Kallal LA (2010) Development of a high-throughput cell-based assay for superoxide production in HL-60 cells. J Biomol Screen 15:388–397

    Article  PubMed  CAS  Google Scholar 

  • Selemidis S, Sobey CG, Wingler K, Schmidt HH, Drummond GR (2008) NADPH oxidases in the vasculature: molecular features, roles in disease and pharmacological inhibition. Pharmacol Ther 120:254–291

    Article  PubMed  CAS  Google Scholar 

  • Shao B, Heinecke JW (2009) HDL, lipid peroxidation, and atherosclerosis. J Lipid Res 50:599–601

    Article  PubMed  CAS  Google Scholar 

  • Sima AV, Botez GM, Stancu CS, Manea A, Raicu M, Simionescu M (2009) Effect of irreversibly glycated LDL in human vascular smooth muscle cells: lipid loading, oxidative and inflammatory stress. J Cell Mol Med. doi:10.1111/j.1582-4934.2009.00933

    PubMed  Google Scholar 

  • Simionescu M (2007) Implications of early structural-functional changes in the endothelium for vascular disease. Arterioscler Thromb Vasc Biol 27:266–274

    Article  PubMed  CAS  Google Scholar 

  • Simionescu M (2009) Cellular dysfunction in inflammatory-related vascular disorders' review series. The inflammatory process: a new dimension of a 19 century old story. J Cell Mol Med 13:4291–4292

    Article  PubMed  Google Scholar 

  • Simionescu M, Popov D, Sima A (2009) Endothelial transcytosis in health and disease. Cell Tissue Res 335:27–40

    Article  PubMed  Google Scholar 

  • Staels B, Fruchart JC (2005) Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 54:2460–2470

    Article  PubMed  CAS  Google Scholar 

  • Tabet F, Schiffrin EL, Callera GE, He Y, Yao G, Ostman A, Kappert K, Tonks NK, Touyz RM (2008) Redox-sensitive signaling by angiotensin II involves oxidative inactivation and blunted phosphorylation of protein tyrosine phosphatase SHP-2 in vascular smooth muscle cells from SHR. Circ Res 103:149–158

    Article  PubMed  CAS  Google Scholar 

  • Teissier E, Nohara A, Chinetti G, Paumelle R, Cariou B, Fruchart JC, Brandes RP, Shah A, Staels B (2004) Peroxisome proliferator-activated receptor alpha induces NADPH oxidase activity in macrophages, leading to the generation of LDL with PPAR-alpha activation properties. Circ Res 95:1174–1182

    Article  PubMed  CAS  Google Scholar 

  • Toba H, Miki S, Shimizu T, Yoshimura A, Inoue R, Sawai N, Tsukamoto R, Murakami M, Morita Y, Nakayama Y, Kobara M, Nakata T (2006) The direct antioxidative and anti-inflammatory effects of peroxisome proliferator-activated receptors ligands are associated with the inhibition of angiotensin converting enzyme expression in streptozotocin-induced diabetic rat aorta. Eur J Pharmacol 549:124–132

    Article  PubMed  CAS  Google Scholar 

  • Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 7:833–846

    Article  PubMed  CAS  Google Scholar 

  • Touyz RM (2003) Reactive oxygen species in vascular biology: role in arterial hypertension. Expert Rev Cardiovasc Ther 1:91–106

    Article  PubMed  CAS  Google Scholar 

  • Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol (Lond) 552:335–344

    Article  CAS  Google Scholar 

  • Unger BS, Patil BM (2009) Apocynin improves endothelial function and prevents the development of hypertension in fructose fed rat. Indian J Pharmacol 41:208–212

    Article  PubMed  CAS  Google Scholar 

  • Ushio-Fukai M, Urao N (2009) Novel role of NADPH oxidase in angiogenesis and stem/progenitor cell function. Antioxid Redox Signal 11:2517–2533

    Article  PubMed  CAS  Google Scholar 

  • Valdivia A, Pérez-Alvarez S, Aroca-Aguilar JD, Ikuta I, Jordán J (2009) Superoxide dismutases: a physiopharmacological update. J Physiol Biochem 65:195–208

    Article  PubMed  CAS  Google Scholar 

  • Vendrov AE, Hakim ZS, Madamanchi NR, Rojas M, Madamanchi C, Runge MS (2007) Atherosclerosis is attenuated by limiting superoxide generation in both macrophages and vessel wall cells. Arterioscler Thromb Vasc Biol 27:2714–2721

    Article  PubMed  CAS  Google Scholar 

  • Vendrov AE, Madamanchi NR, Niu XL, Molnar KC, Runge M, Szyndralewiez C, Page P, Runge MS (2010) NADPH oxidases regulate CD44 and hyaluronic acid expression in thrombin-treated vascular smooth muscle cells and in atherosclerosis. J Biol Chem 285:26545–26557

    Article  PubMed  CAS  Google Scholar 

  • Wind S, Beuerlein K, Armitage ME, Taye A, Kumar AH, Janowitz D, Neff C, Shah AM, Wingler K, Schmidt HH (2010) Oxidative stress and endothelial dysfunction in aortas of aged spontaneously hypertensive rats by NOX1/2 is reversed by NADPH oxidase inhibition. Hypertension 56:490–497

    Article  PubMed  CAS  Google Scholar 

  • Wingler K, Wünsch S, Kreutz R, Rothermund L, Paul M, Schmidt HH (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 31:1456–1464

    Article  PubMed  CAS  Google Scholar 

  • Wolin MS (2004) Subcellular localization of Nox-containing oxidases provides unique insight into their role in vascular oxidant signaling. Arterioscler Thromb Vasc Biol 24:625–627

    Article  PubMed  CAS  Google Scholar 

  • Wolin MS, Ahmad M, Gupte SA (2005) Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH. Am J Physiol Lung Cell Mol Physiol 289:159–170

    Article  CAS  Google Scholar 

  • Wong CM, Cheema AK, Zhang L, Suzuki YJ (2008) Protein carbonylation as a novel mechanism in redox signaling. Circ Res 102:310–318

    Article  PubMed  CAS  Google Scholar 

  • Woo HA, Yim SH, Shin DH, Kang D, Yu DY, Rhee SG (2010) Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. Cell 140:517–528

    Article  PubMed  CAS  Google Scholar 

  • Wu RF, Xu YC, Ma Z, Nwariaku FE, Sarosi GA Jr, Terada LS (2005) Subcellular targeting of oxidants during endothelial cell migration. J Cell Biol 171:893–904

    Article  PubMed  CAS  Google Scholar 

  • Wu WS, Wu JR, Hu CT (2008) Signal cross talks for sustained MAPK activation and cell migration: the potential role of reactive oxygen species. Cancer Metastasis Rev 27:303–314

    Article  PubMed  CAS  Google Scholar 

  • Xu X, Gao X, Potter BJ, Cao JM, Zhang C (2007) Anti-LOX-1 rescues endothelial function in coronary arterioles in atherosclerotic ApoE knockout mice. Arterioscler Thromb Vasc Biol 27:871–877

    Article  PubMed  CAS  Google Scholar 

  • Yamamori T, Inanami O, Nagahata H, Kuwabara M (2004) Phosphoinositide 3-kinase regulates the phosphorylation of NADPH oxidase component p47(phox) by controlling cPKC/PKCdelta but not Akt. Biochem Biophys Res Commun 316:720–730

    Article  PubMed  CAS  Google Scholar 

  • Zadák Z, Hyspler R, Tichá A, Hronek M, Fikrová P, Rathouská J, Hrnciariková D, Stetina R (2009) Antioxidants and vitamins in clinical conditions. Physiol Res 58:13–17

    Google Scholar 

  • Zalba G, Fortuño A, San José G, Moreno MU, Beloqui O, Díez J (2007) Oxidative stress, endothelial dysfunction and cerebrovascular disease. Cerebrovasc Dis 24:24–29

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Sheppard OR, Shah AM, Brewer AC (2008) Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F. Free Radic Biol Med 45:679–685

    Article  PubMed  CAS  Google Scholar 

  • Zhao R, Ma X, Xie X, Shen GX (2009) Involvement of NADPH oxidase in oxidized LDL-induced upregulation of heat shock factor-1 and plasminogen activator inhibitor-1 in vascular endothelial cells. Am J Physiol Endocrinol Metab 297:104–111

    Article  CAS  Google Scholar 

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Acknowledgments

This research was financially supported by European Social Fund, “Cristofor I. Simionescu” Postdoctoral Fellowship Programme (ID POSDRU/89/1.5/S/55216), Sectoral Operational Programme Human Resources Development 2007–2013, and Romanian Ministry of Education, and Research (CNCSIS-UEFISCSU PNII-TE project number 65/2010).

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Manea, A. NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology. Cell Tissue Res 342, 325–339 (2010). https://doi.org/10.1007/s00441-010-1060-y

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