Abstract
Choroidal neovascularization (CNV) occurs in a variety of chorioretinal diseases including age-related macular degeneration (AMD) and is the major cause of severe visual loss in patients with AMD. Oxidative stress has been thought to play an important role in the development of CNV, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as one of the major intracellular sources of reactive oxygen species (ROS) in the vascular system is a logical candidate as a central player. In this chapter, we review the role of p22phox, an integral subunit in the NADPH oxidase complex, in the mouse eye in relation to CNV. We show that p22phox is expressed in the retinal pigment epithelial (RPE) cells and inner retinal neurons and that a small-interfering RNA (siRNA) designed against p22phox efficiently reduces the expression of the protein in the retina when delivered by means of recombinant adeno-associated virus (AAV) vector. Vector treatment inhibited CNV in the mouse when delivered into the subretinal space where RPE cells were transduced. These results suggest that NADPH oxidase-mediated ROS production in RPE cells may play an important role in the pathogenesis of neovascular AMD, and that this pathway may represent a new target for its therapeutic intervention.
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References
Klein R (2007) Overview of progress in the epidemiology of age-related macular degeneration. Ophthalmic Epidemiol 14(4):184–187
Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE, Hofman A, Jensen S, Wang JJ, de Jong PT (2001) Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 108(4):697–704
Seddon JM, Chen CA (2004) The epidemiology of age-related macular degeneration. Int Ophthalmol Clin 44(4):17–39
de Jong PT (2006) Age-related macular degeneration. N Engl J Med 355(14):1474–1485
Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82(11):844–851
Friedman DS, O’Colmain BJ, Munoz B, Tomany SC, McCarty C, de Jong PT, Nemesure B, Mitchell P, Kempen J (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122(4):564–572
Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45(2):115–134
Khandhadia S, Lotery A (2010) Oxidation and age-related macular degeneration: insights from molecular biology. Expert Rev Mol Med 12:e34
Miceli MV, Liles MR, Newsome DA (1994) Evaluation of oxidative processes in human pigment epithelial cells associated with retinal outer segment phagocytosis. Exp Cell Res 214(1):242–249
Yang D, Elner SG, Bian ZM, Till GO, Petty HR, Elner VM (2007) Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res 85(4):462–472
Tate DJ Jr, Miceli MV, Newsome DA (1995) Phagocytosis and H2O2 induce catalase and metallothionein gene expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 36(7):1271–1279
Age-Related Eye Disease Study Research Group (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 119(10):1417–1436
(2001) Dietary supplements reduce risk of vision loss from age-related macular degeneration. Optom Vis Sci 78(12):856
Wang Y, Wang VM, Chan CC (2011) The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment. Eye (Lond) 25(2):127–139
Liutkeviciene R, Lesauskaite V, Asmoniene V, Zaliuniene D, Jasinskas V (2010) Factors determining age-related macular degeneration: a current view. Medicina (Kaunas) 46(2):89–94
Ding X, Patel M, Chan CC (2009) Molecular pathology of age-related macular degeneration. Prog Retin Eye Res 28(1):1–18
Patel M, Chan CC (2008) Immunopathological aspects of age-related macular degeneration. Semin Immunopathol 30(2):97–110
Biswas SK, Rahman I (2009) Environmental toxicity, redox signaling and lung inflammation: the role of glutathione. Mol Aspects Med 30(1–2):60–76
Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG, Perez VL (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14(2):194–198
Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82(1):47–95
Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120(4):483–495
Gonzalez FJ (2005) Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. Mutat Res 569(1–2):101–110
Gottlieb RA (2003) Cytochrome P450: major player in reperfusion injury. Arch Biochem Biophys 420(2):262–267
Harrison R (2004) Physiological roles of xanthine oxidoreductase. Drug Metab Rev 36(2): 363–375
Mata-Greenwood E, Jenkins C, Farrow KN, Konduri GG, Russell JA, Lakshminrusimha S, Black SM, Steinhorn RH (2006) eNOS function is developmentally regulated: uncoupling of eNOS occurs postnatally. Am J Physiol Lung Cell Mol Physiol 290(2):L232–L241
Mueller CF, Laude K, McNally JS, Harrison DG (2005) ATVB in focus: redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol 25(2):274–278
Pritchard KA Jr, Ackerman AW, Gross ER, Stepp DW, Shi Y, Fontana JT, Baker JE, Sessa WC (2001) Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase. J Biol Chem 276(21):17621–17624
Schrader M, Fahimi HD (2004) Mammalian peroxisomes and reactive oxygen species. Histochem Cell Biol 122(4):383–393
Thannickal VJ, Fanburg BL (2000) Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279(6):L1005–L1028
Babior BM (1999) NADPH oxidase: an update. Blood 93(5):1464–1476
Babior BM (2004) NADPH oxidase. Curr Opin Immunol 16(1):42–47
Cross AR, Segal AW (2004) The NADPH oxidase of professional phagocytes–prototype of the NOX electron transport chain systems. Biochim Biophys Acta 1657(1):1–22
Babior BM (2000) The NADPH oxidase of endothelial cells. IUBMB Life 50(4–5):267–269
Gorlach A, Brandes RP, Nguyen K, Amidi M, Dehghani F, Busse R (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(1):26–32
West IC (2000) Radicals and oxidative stress in diabetes. Diabet Med 17(3):171–180
Giugliano D, Ceriello A, Paolisso G (1996) Oxidative stress and diabetic vascular complications. Diabetes Care 19(3):257–267
Jay D, Hitomi H, Griendling KK (2006) Oxidative stress and diabetic cardiovascular complications. Free Radic Biol Med 40(2):183–192
Ushio-Fukai M, Urao N (2009) Novel role of NADPH oxidase in angiogenesis and stem/progenitor cell function. Antioxid Redox Signal 11(10):2517–2533
Guzik TJ, Griendling KK (2009) NADPH oxidases: molecular understanding finally reaching the clinical level? Antioxid Redox Signal 11(10):2365–2370
Frey RS, Ushio-Fukai M, Malik AB (2009) NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology. Antioxid Redox Signal 11(4):791–810
Lassegue B, Griendling KK (2009) NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol 30(4):653–661
Gao L, Mann GE (2009) Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. Cardiovasc Res 82(1):9–20
De Leo FR, Ulman KV, Davis AR, Jutila KL, Quinn MT (1996) Assembly of the human neutrophil NADPH oxidase involves binding of p67phox and flavocytochrome b to a common functional domain in p47phox. J Biol Chem 271(29):17013–17020
Segal AW, Abo A (1993) The biochemical basis of the NADPH oxidase of phagocytes. Trends Biochem Sci 18(2):43–47
Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313
Van Buul JD, Fernandez-Borja M, Anthony EC, Hordijk PL (2005) Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Antioxid Redox Signal 7(3–4):308–317
Lyle AN, Griendling KK (2006) Modulation of vascular smooth muscle signaling by reactive oxygen species. Physiology (Bethesda) 21:269–280
Ushio-Fukai M (2009) Compartmentalization of redox signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal 11(6):1289–1299
Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86(5):494–501
Petry A, Weitnauer M, Gorlach A (2010) Receptor activation of NADPH oxidases. Antioxid Redox Signal 13(4):467–487
Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, Channon KM (2002) Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105(14):1656–1662
Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88(2): E14–E22
Al-Shabrawey M, Rojas M, Sanders T, Behzadian A, El-Remessy A, Bartoli M, Parpia AK, Liou G, Caldwell RB (2008) Role of NADPH oxidase in retinal vascular inflammation. Invest Ophthalmol Vis Sci 49(7):3239–3244
McNally JS, Davis ME, Giddens DP, Saha A, Hwang J, Dikalov S, Jo H, Harrison DG (2003) Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol 285(6):H2290–H2297
Doughan AK, Harrison DG, Dikalov SI (2008) Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 102(4):488–496
Lassegue B, Griendling KK (2004) Reactive oxygen species in hypertension; an update. Am J Hypertens 17(9):852–860
Grimm D, Streetz KL, Jopling CL, Storm TA, Pandey K, Davis CR, Marion P, Salazar F, Kay MA (2006) Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441(7092):537–541
Mori K, Gehlbach P, Yamamoto S, Duh E, Zack DJ, Li Q, Berns KI, Raisler BJ, Hauswirth WW, Campochiaro PA (2002) AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci 43(6):1994–2000
Al-Shabrawey M, Bartoli M, El-Remessy AB, Platt DH, Matragoon S, Behzadian MA, Caldwell RW, Caldwell RB (2005) Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. Am J Pathol 167(2):599–607
Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11(1):81–128
Ischiropoulos H, Zhu L, Chen J, Tsai M, Martin JC, Smith CD, Beckman JS (1992) Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch Biochem Biophys 298(2):431–437
Bok D (1993) The retinal pigment epithelium: a versatile partner in vision. J Cell Sci Suppl 17:189–195
Rizzolo LJ (1997) Polarity and the development of the outer blood-retinal barrier. Histol Histopathol 12(4):1057–1067
Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8(9–10):1583–1596
Kawahara BT, Quinn MT, Lambeth JD (2007) Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes. BMC Evol Biol 7:109
Harfouche R, Malak NA, Brandes RP, Karsan A, Irani K, Hussain SN (2005) Roles of reactive oxygen species in angiopoietin-1/tie-2 receptor signaling. Faseb J 19(12):1728–1730
Ushio-Fukai M, Alexander RW (2004) Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem 264(1–2):85–97
Ushio-Fukai M (2006) Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 71(2):226–235
Ushio-Fukai M (2007) VEGF signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal 9(6):731–739
Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT (1997) Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol 81(2):154–162
Ryan SJ (1982) Subretinal neovascularization. Natural history of an experimental model. Arch Ophthalmol 100(11):1804–1809
Yi X, Ogata N, Komada M, Yamamoto C, Takahashi K, Omori K, Uyama M (1997) Vascular endothelial growth factor expression in choroidal neovascularization in rats. Graefes Arch Clin Exp Ophthalmol 235(5):313–319
Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845–881
Campochiaro PA (2000) Retinal and choroidal neovascularization. J Cell Physiol 184(3): 301–310
Das A, McGuire PG (2003) Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition. Prog Retin Eye Res 22(6):721–748
Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 20(6):705–732
Kent D, Sheridan C (2003) Choroidal neovascularization: a wound healing perspective. Mol Vis 9:747–755
Mousa SA, Lorelli W, Campochiaro PA (1999) Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells. J Cell Biochem 74(1):135–143
Peng PH, Ko ML, Chen CF, Juan SH (2008) Haem oxygenase-1 gene transfer protects retinal ganglion cells from ischaemia/reperfusion injury. Clin Sci (Lond) 115(11):335–342
Zheng L, Gong B, Hatala DA, Kern TS (2007) Retinal ischemia and reperfusion causes capillary degeneration: similarities to diabetes. Invest Ophthalmol Vis Sci 48(1):361–367
Aslan M, Cort A, Yucel I (2008) Oxidative and nitrative stress markers in glaucoma. Free Radic Biol Med 45(4):367–376
Kamsler A, Segal M (2004) Hydrogen peroxide as a diffusible signal molecule in synaptic plasticity. Mol Neurobiol 29(2):167–178
Thiels E, Klann E (2002) Hippocampal memory and plasticity in superoxide dismutase mutant mice. Physiol Behav 77(4–5):601–605
Vallet P, Charnay Y, Steger K, Ogier-Denis E, Kovari E, Herrmann F, Michel JP, Szanto I (2005) Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Neuroscience 132(2):233–238
Zimmerman MC, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, Davisson RL (2002) Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res 91(11):1038–1045
Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4(3):181–189
Li JM, Shah AM (2004) Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287(5):R1014–R1030
Cacicedo JM, Benjachareowong S, Chou E, Ruderman NB, Ido Y (2005) Palmitate-induced apoptosis in cultured bovine retinal pericytes: roles of NAD(P)H oxidase, oxidant stress, and ceramide. Diabetes 54(6):1838–1845
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(9):723–734
Ellis EA, Grant MB, Murray FT, Wachowski MB, Guberski DL, Kubilis PS, Lutty GA (1998) Increased NADH oxidase activity in the retina of the BBZ/Wor diabetic rat. Free Radic Biol Med 24(1):111–120
Saito Y, Geisen P, Uppal A, Hartnett ME (2007) Inhibition of NAD(P)H oxidase reduces apoptosis and avascular retina in an animal model of retinopathy of prematurity. Mol Vis 13:840–853
Rodrigues EB (2007) Inflammation in dry age-related macular degeneration. Ophthalmologica 221(3):143–152
Acknowledgments
We acknowledge NIH grants EY13729, EY11123, EY08571, and grants from the Macular Vision Research Foundation, Foundation Fighting Blindness, Juvenile Diabetes Research Foundation, and Research to Prevent Blindness, Inc. American Diabetes Association for partial support of this work. W.W.H. and the University of Florida have a financial interest in the use of AAV therapies, and own equity in a company (AGTC Inc.) that might, in the future, commercialize some aspects of this work. We thank Mike Daniel for help with statistic analysis, and Clay Smith for help with Western blot analysis.
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Li, Q., Verma, A., Dinculescu, A., Lewin, A.S., Hauswirth, W.W. (2012). NADPH Oxidase in Choroidal Neovascularization. In: Stratton, R., Hauswirth, W., Gardner, T. (eds) Studies on Retinal and Choroidal Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press. https://doi.org/10.1007/978-1-61779-606-7_14
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