Oxidative Stress, Nox Isoforms and Complications of Diabetes—Potential Targets for Novel Therapies

  • Mona Sedeek
  • Augusto C. Montezano
  • Richard L. Hebert
  • Stephen P. Gray
  • Elyse Di Marco
  • Jay C. Jha
  • Mark E. Cooper
  • Karin Jandeleit-Dahm
  • Ernesto L. Schiffrin
  • Jennifer L. Wilkinson-Berka
  • Rhian M. Touyz


Most diabetes-related complications and causes of death arise from cardiovascular disease and end-stage renal disease. Amongst the major complications of diabetes mellitus are retinopathy, neuropathy, nephropathy and accelerated atherosclerosis. Increased bioavailability of reactive oxygen species (ROS) (termed oxidative stress), derived in large part from the NADPH oxidase (Nox) family of free radical producing enzymes, has been demonstrated in experimental and clinical diabetes and has been implicated in the cardiovascular and renal complications of diabetes. The present review focuses on the role of Noxs and oxidative stress in some major complications of diabetes, including nephropathy, retinopathy and atherosclerosis. We also discuss Nox isoforms as potential targets for therapy.


Diabetic nephropathy Cardiovascular disease NADPH oxidase Diabetes mellitus Nox isoforms 


  1. 1.
    Emerging Risk Factors Collaboration, Sarwar, N., Gao, P., Seshasai, S. R., Gobin, R., Kaptoge, S., et al. (2010). Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet, 375, 2215–2222.PubMedCrossRefGoogle Scholar
  2. 2.
    Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, (2011). Atlanta: Department of Health and Human Services, Centers for Disease Control and Prevention.Google Scholar
  3. 3.
    Ismail-Beigi, F. (2012). Clinical practice. Glycemic management of type 2 diabetes mellitus. The New England Journal of Medicine, 366(14), 1319–1327.PubMedCrossRefGoogle Scholar
  4. 4.
    Tikellis, C., Pickering, R.J., Tsorotes, D., Du, X.J., Kiriazis, H., Nguyen-Huu, T.P., Head, G.A., Cooper, M.E., Thomas, M.C. (2012) The interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes. Clinical Science (London) [Epub ahead of print].Google Scholar
  5. 5.
    Huang, A., Yang, Y. M., Feher, A., Bagi, Z., Kaley, G., & Sun, D. (2012). Exacerbation of endothelial dysfunction during the progression of diabetes: role of oxidative stress. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 302(6), R674–R681.PubMedCrossRefGoogle Scholar
  6. 6.
    Chang, C.M., Hsieh, C.J., Huang, J.C., Huang, I.C. (2012). Acute and chronic fluctuations in blood glucose levels can increase oxidative stress in type 2 diabetes mellitus. Acta Diabetologia. 2012 May 1. [Epub ahead of print].Google Scholar
  7. 7.
    Tang, W. H., Martin, K. A., & Hwa, J. (2012). Aldose reductase, oxidative stress, and diabetic mellitus. Frontiers in Pharmacology, 3, 87–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Whaley-Connell, A., Sowers, J.R. (2012). Oxidative stress in the cardiorenal metabolic syndrome. Current Hypertension Reports. May 13. [Epub ahead of print].Google Scholar
  9. 9.
    Coughlan, M. T., Patel, S. K., Jerums, G., Penfold, S. A., Nguyen, T. V., Sourris, K. C., et al. (2011). Advanced glycation urinary protein-bound biomarkers and severity of diabetic nephropathy in man. American Journal of Nephrology, 34(4), 347–355.PubMedCrossRefGoogle Scholar
  10. 10.
    Jay, D., Hitomi, H., & Griendling, K. K. (2006). Oxidative stress and diabetic cardiovascular complications. Free Radical Biology & Medicine, 40(2), 183–192.CrossRefGoogle Scholar
  11. 11.
    Luther, J. M., & Brown, N. (2011). The renin–angiotensin–aldosterone system and glucose homeostasis. Trends in Pharmacological Sciences, 32(12), 734–739.PubMedCrossRefGoogle Scholar
  12. 12.
    Shen, G. X. (2010). Oxidative stress and diabetic cardiovascular disorders: roles of mitochondria and NADPH oxidase. Canadian Journal of Physiology and Pharmacology, 88(3), 241–248.PubMedCrossRefGoogle Scholar
  13. 13.
    Thum, T., Fraccarollo, D., Schultheiss, M., Froese, S., Galuppo, P., Widder, J. D., et al. (2007). Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes, 56(3), 666–674.PubMedCrossRefGoogle Scholar
  14. 14.
    Babior, B. M. (2004). NADPH oxidase. Current Opinion in Immunology, 16(1), 42–47.PubMedCrossRefGoogle Scholar
  15. 15.
    Al Ghouleh, I., Khoo, N. K., Knaus, U. G., Griendling, K. K., Touyz, R. M., Thannickal, V. J., et al. (2011). Oxidases and peroxidases in cardiovascular and lung disease: new concepts in reactive oxygen species signaling. Free Radical Biology & Medicine, 1, 1271–1288.CrossRefGoogle Scholar
  16. 16.
    Dworakowski, R., Alom-Ruiz, S. P., & Shah, A. M. (2008). NADPH oxidase-derived reactive oxygen species in the regulation of endothelial phenotype. Pharmacological Reports, 60(1), 21–28.PubMedGoogle Scholar
  17. 17.
    Sirker, A., Zhang, M., & Shah, A. M. (2011). NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies. Basic Research in Cardiology, 106(5), 735–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Redmond, E. M., & Cahill, P. A. (2012). The NOX–ROS connection: targeting Nox1 control of N-cadherin shedding in vascular smooth muscle cells. Cardiovascular Research, 93(3), 386–390.PubMedCrossRefGoogle Scholar
  19. 19.
    Dikalova, A. E., Góngora, M. C., Harrison, D. G., Lambeth, J. D., Dikalov, S., & Griendling, K. K. (2010). Upregulation of Nox1 in vascular smooth muscle leads to impaired endothelium-dependent relaxation via eNOS uncoupling. American Journal of Physiology—Heart and Circulatory Physiology, 299(3), H673–H679.PubMedCrossRefGoogle Scholar
  20. 20.
    Bayat, H., Schröder, K., Pimentel, D. R., Brandes, R. P., Verbeuren, T. J., Cohen, R. A., et al. (2012). Activation of thromboxane receptor modulates interleukin-1β-induced monocyte adhesion—a novel role of Nox1. Free Radical Biology & Medicine, 52(9), 1760–1766.CrossRefGoogle Scholar
  21. 21.
    Yogi, A., Mercure, C., Touyz, J., Callera, G. E., Montezano, A. C., Aranha, A. B., et al. (2008). Renal redox-sensitive signaling, but not blood pressure, is attenuated by Nox1 knockout in angiotensin II-dependent chronic hypertension. Hypertension, 51(2), 500–506.PubMedCrossRefGoogle Scholar
  22. 22.
    Paik, Y. H., Iwaisako, K., Seki, E., Inokuchi, S., Schnabl, B., Osterreicher, C. H., et al. (2011). The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology, 53(5), 1730–1741.PubMedCrossRefGoogle Scholar
  23. 23.
    Yasuda, M., Kato, S., Yamanaka, N., Iimori, M., Utsumi, D., Kitahara, Y., et al. (2012). Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice. American Journal of Physiology—Gastrointestinal and Liver Physiology, 302(10), G1133–G1142.PubMedCrossRefGoogle Scholar
  24. 24.
    Sheehan, A. L., Carrell, S., Johnson, B., Stanic, B., Banfi, B., & Miller, F. J., Jr. (2011). Role for Nox1 NADPH oxidase in atherosclerosis. Atherosclerosis, 216(2), 321–326.PubMedCrossRefGoogle Scholar
  25. 25.
    Youn, J.Y., Gao, L., Cai, H. (2012). The p47(phox)- and NADPH oxidase organiser 1 (NOXO1)-dependent activation of NADPH oxidase 1 (NOX1) mediates endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction in a streptozotocin-induced murine model of diabetes. Diabetologia 55, 2069–2079.Google Scholar
  26. 26.
    Liu, J., Ormsby, A., Oja-Tebbe, N., & Pagano, P. J. (2004). Gene transfer of NAD(P)H oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy. Circulation Research, 95(6), 587–594.PubMedCrossRefGoogle Scholar
  27. 27.
    Touyz, R. M., Mercure, C., He, Y., Javeshghani, D., Yao, G., & Reudelhuber, T. (2005). Angiotensin II-dependent chronic hypertension and cardiac hypertrophy in mice do not require gp91phox-containing NADPH oxidase. Hypertension, 45, 530–537.PubMedCrossRefGoogle Scholar
  28. 28.
    Syed, I., Kyathanahalli, C. N., Jayaram, B., Govind, S., Rhodes, C. J., Kowluru, R. A., et al. (2011). Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet. Diabetes, 60(11), 2843–2852.PubMedCrossRefGoogle Scholar
  29. 29.
    Mukherjea, D., Jajoo, S., Sheehan, K., Kaur, T., Sheth, S., Bunch, J., et al. (2011). NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss. Antioxidants & Redox Signaling, 14(6), 999–1010.CrossRefGoogle Scholar
  30. 30.
    Chen, G., Adeyemo, A. A., Zhou, J., Chen, Y., Doumatey, A., Lashley, K., et al. (2007). A genome-wide search for linkage to renal function phenotypes in West Africans with type 2 diabetes. American Journal of Kidney Diseases, 49(3), 394–400.PubMedCrossRefGoogle Scholar
  31. 31.
    Ye, S., Zhong, H., Yanamadala, S., & Campese, V. M. (2006). Oxidative stress mediates the stimulation of sympathetic nerve activity in the phenol renal injury model of hypertension. Hypertension, 48(2), 309–132.PubMedCrossRefGoogle Scholar
  32. 32.
    Streeter, J., Thiel, W., Brieger, K., Miller, Jr F. J. (2012). Opportunity Nox: the future of NADPH oxidases as therapeutic targets in cardiovascular disease. Cardiovascular Therapeutics. doi: 10.1111.Google Scholar
  33. 33.
    Xi, G., Shen, X., Maile, L. A., Wai, C., Gollahon, K., & Clemmons, D. R. (2012). Hyperglycemia enhances IGF-I-stimulated Src activation via increasing Nox4-derived reactive oxygen species in a PKCζ-dependent manner in vascular smooth muscle cells. Diabetes, 61(1), 104–113.PubMedCrossRefGoogle Scholar
  34. 34.
    Fulton, D. J. (2009). Nox5 and the regulation of cellular function. Antioxidants & Redox Signaling, 11(10), 2443–2452.CrossRefGoogle Scholar
  35. 35.
    Lyle, A. N., Deshpande, N. N., Taniyama, Y., Seidel-Rogol, B., Pounkova, L., Du, P., et al. (2009). Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circulation Research, 105(3), 249–259.PubMedCrossRefGoogle Scholar
  36. 36.
    Martin-Garrido, A., Brown, D. I., Lyle, A. N., Dikalova, A., Seidel-Rogol, B., Lassègue, B., et al. (2011). NADPH oxidase 4 mediates TGF-β-induced smooth muscle α-actin via p38MAPK and serum response factor. Free Radical Biology & Medicine, 50(2), 354–356.CrossRefGoogle Scholar
  37. 37.
    Takac, I., Schröder, K., Zhang, L., Lardy, B., Anilkumar, N., Lambeth, J. D., et al. (2011). The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. Journal of Biological Chemistry, 286(15), 13304–13313.PubMedCrossRefGoogle Scholar
  38. 38.
    Schröder, K., Zhang, M., Benkhoff, S., Mieth, A., Pliquett, R., Kosowski, J., et al. (2012). Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circulation Research, 110, 1217–1225.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang, M., Brewer, A. C., Schröder, K., Santos, C. X., Grieve, D. J., Wang, M., et al. (2010). NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proceedings of the National Academy of Sciences of the United States of America, 107(42), 18121–18126.PubMedCrossRefGoogle Scholar
  40. 40.
    Kuroda, J., Ago, T., Matsushima, S., Zhai, P., Schneider, M. D., & Sadoshima, J. (2010). NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proceedings of the National Academy of Sciences of the United States of America, 107(35), 15565–15570.PubMedCrossRefGoogle Scholar
  41. 41.
    Tong, X., Hou, X., Jourd’heuil, D., Weisbrod, R. M., & Cohen, R. A. (2010). Upregulation of Nox4 by TGF{beta}1 oxidizes SERCA and inhibits NO in arterial smooth muscle of the prediabetic Zucker rat. Circulation Research, 107, 975–983.PubMedCrossRefGoogle Scholar
  42. 42.
    Wu, X., & Williams, K. J. (2012). NOX4 pathway as a source of selective insulin resistance and responsiveness. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(5), 1236–1245.PubMedCrossRefGoogle Scholar
  43. 43.
    Maalouf, R. M., Eid, A. A., Gorin, Y. C., Block, K., Escobar, G. P., Bailey, S., et al. (2012). Nox4-derived reactive oxygen species mediate cardiomyocyte injury in early type 1 diabetes. American Journal of Physiology. Cell Physiology, 302(3), C597–C604.PubMedCrossRefGoogle Scholar
  44. 44.
    Piwkowska, A., Rogacka, D., Audzeyenka, I., Jankowski, M., & Angielski, S. (2011). High glucose concentration affects the oxidant–antioxidant balance in cultured mouse podocytes. Journal of Cellular Biochemistry, 112(6), 1661–1672.PubMedCrossRefGoogle Scholar
  45. 45.
    Sedeek, M., Callera, G., Montezano, A., Gutsol, A., Heitz, F., Szyndralewiez, C., et al. (2010). Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. American Journal of Physiology. Renal Physiology, 299(6), F1348–F1358.PubMedCrossRefGoogle Scholar
  46. 46.
    Montezano, A. C., Buger, D., Ceravolo, G. S., Yusuf, H., Montero, M., & Touyz, R. M. (2011). Novel Noxes homologues in the vasculature: focusing on Nox4 and Nox5. Clinical Science, 120(4), 131–141.PubMedCrossRefGoogle Scholar
  47. 47.
    Pandey, D., & Fulton, D. J. (2011). Molecular regulation of NADPH oxidase 5 via the MAPK pathway. American Journal of Physiology—Heart and Circulatory Physiology, 300(4), H1336–4.PubMedCrossRefGoogle Scholar
  48. 48.
    Manea, A., Manea, S. A., Florea, I. C., Luca, C. M., & Raicu, M. (2012). Positive regulation of NADPH oxidase 5 by proinflammatory-related mechanisms in human aortic smooth muscle cells. Free Radical Biology & Medicine, 52(9), 1497–1507.CrossRefGoogle Scholar
  49. 49.
    Hahn, N. E., Meischl, C., Kawahara, T., Musters, R. J., Verhoef, V. M., van der Velden, J., et al. (2012). NOX5 expression is increased in intramyocardial blood vessels and cardiomyocytes after acute myocardial infarction in humans. American Journal of Pathology, 180(6), 2222–2229.PubMedCrossRefGoogle Scholar
  50. 50.
    Pandey, D., Patel, A., Patel, V., Chen, F., Qian, J., Wang, Y., Barman, S.A., Venema, R.C., Stepp, D.W., Rudic, R.D., Fulton, D.J. (2012). Expression and functional significance of NADPH oxidase 5 (Nox5) and its splice variants in human blood vessels. American Journal of Physiology—Heart and CirculatoryPhysiology, 302(10), H1919–28.Google Scholar
  51. 51.
    Bhavani, N. (2011). Transient congenital hypothyroidism. Indian Journal of Endocrinology and Metabolism, 15(Suppl 2), S117–S120.PubMedCrossRefGoogle Scholar
  52. 52.
    Cooper, M. E. (1998). Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet, 352(9123), 213–219.PubMedCrossRefGoogle Scholar
  53. 53.
    Forbes, J. M., Coughlan, M. T., & Cooper, M. E. (2008). Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes, 57(6), 1446–1454.PubMedCrossRefGoogle Scholar
  54. 54.
    Eid, A. A., Gorin, Y., Faff, B. M., Maalouf, R., Barnes, J. L., Block, K., et al. (2009). Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes, 58(5), 1201–1211.PubMedCrossRefGoogle Scholar
  55. 55.
    Etoh, T., Inoguchi, T., Kakimoto, M., Sonoda, N., Kobayashi, K., Kuroda, J., et al. (2003). Increased expression of NAD(P)H oxidase subunits, NOX4 and p22phox, in the kidney of streptozotocin-induced diabetic rats and its reversibility by interventive insulin treatment. Diabetologia, 46(10), 1428–1437.PubMedCrossRefGoogle Scholar
  56. 56.
    Asaba, K., Tojo, A., Onozato, M. L., Goto, A., Quinn, M. T., Fujita, T., et al. (2005). Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney International, 67(5), 1890–1898.PubMedCrossRefGoogle Scholar
  57. 57.
    Kitada, M., Koya, D., Sugimoto, T., Isono, M., Araki, S., Kashiwagi, A., et al. (2003). Translocation of glomerular p47phox and p67phox by protein kinase C-beta activation is required for oxidative stress in diabetic nephropathy. Diabetes, 52(10), 2603–2614.PubMedCrossRefGoogle Scholar
  58. 58.
    Ohshiro, Y., Ma, R. C., Yasuda, Y., Hiraoka-Yamamoto, J., Clermont, A. C., Isshiki, K., et al. (2006). Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice. Diabetes, 55(11), 3112–3120.PubMedCrossRefGoogle Scholar
  59. 59.
    Cai, W., Torreggiani, M., Zhu, L., Chen, X., He, J. C., Striker, G. E., et al. (2010). AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-delta: implications for vascular disease. American Journal of Physiology. Cell Physiology, 298(3), C624–C634.PubMedCrossRefGoogle Scholar
  60. 60.
    Lee, H. B., Yu, M. R., Yang, Y., Jiang, Z., & Ha, H. (2003). Reactive oxygen species-regulated signaling pathways in diabetic nephropathy. Journal of the American Society of Nephrology, 14(8 Suppl 3), S241–S245.PubMedCrossRefGoogle Scholar
  61. 61.
    Gorin, Y., Ricono, J. M., Kim, N. H., Bhandari, B., Choudhury, G. G., & Abboud, H. E. (2003). Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. American Journal of Physiology. Renal Physiology, 285(2), F219–F229.PubMedGoogle Scholar
  62. 62.
    Nava, M., Quiroz, Y., Vaziri, N., & Rodriguez-Iturbe, B. (2003). Melatonin reduces renal interstitial inflammation and improves hypertension in spontaneously hypertensive rats. American Journal of Physiology. Renal Physiology, 284(3), F447–F454.PubMedGoogle Scholar
  63. 63.
    Ha, H., Yu, M. R., Choi, Y. J., Kitamura, M., & Lee, H. B. (2002). Role of high glucose-induced nuclear factor-kappaB activation in monocyte chemoattractant protein-1 expression by mesangial cells. Journal of the American Society of Nephrology, 13(4), 894–902.PubMedGoogle Scholar
  64. 64.
    Weigert, C., Sauer, U., Brodbeck, K., Pfeiffer, A., Häring, H. U., & Schleicher, E. D. (2000). AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-beta1 promoter in mesangial cells. Journal of the American Society of Nephrology, 11(11), 2007–2016.PubMedGoogle Scholar
  65. 65.
    Kim, N. H., Rincon-Choles, H., Bhandari, B., Choudhury, G. G., Abboud, H. E., & Gorin, Y. (2006). Redox dependence of glomerular epithelial cell hypertrophy in response to glucose. American Journal of Physiology. Renal Physiology, 290(3), F741–F751.PubMedCrossRefGoogle Scholar
  66. 66.
    Susztak, K., Raff, A. C., Schiffer, M., & Böttinger, E. P. (2006). Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes, 55(1), 225–233.PubMedCrossRefGoogle Scholar
  67. 67.
    Yau, J. W., Rogers, S. L., Kawasaki, R., Lamoureux, E. L., Kowalski, J. W., Bek, T., Wong, T. Y., & Meta-Analysis for Eye Disease (META-EYE) Study Group. (2012). Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care, 35(3), 556–564.PubMedCrossRefGoogle Scholar
  68. 68.
    Wilkinson, C. P., Ferris, F. L., 3rd, Klein, R. E., Lee, P. P., Agardh, C. D., Davis, M., et al. (2003). Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology, 110, 1677–1682.PubMedCrossRefGoogle Scholar
  69. 69.
    Arden, G. B., & Sivaprasad, S. (2011). Hypoxia and oxidative stress in the causation of diabetic retinopathy. Current Diabetes Reviews, 7, 291–304.PubMedGoogle Scholar
  70. 70.
    Al-Shabrawey, M., Bartoli, M., El-Remessy, A. B., Ma, G., Matragoon, S., Lemtalsi, T., et al. (2008). Role of NADPH oxidase and Stat3 in statin-mediated protection against diabetic retinopathy. Investigative Ophthalmology and Visual Science, 49, 3231–3238.PubMedCrossRefGoogle Scholar
  71. 71.
    Li, J., Wang, J. J., Yu, Q., Chen, K., Mahadev, K., & Zhang, S. X. (2010). Inhibition of reactive oxygen species by Lovastatin downregulates vascular endothelial growth factor expression and ameliorates blood–retinal barrier breakdown in db/db mice: role of NADPH oxidase 4. Diabetes, 59, 1528–1538.PubMedCrossRefGoogle Scholar
  72. 72.
    Dvoriantchikova et al. (2012) Neuronal NAD(P)H oxidases contribute to ROS production and mediate RGC death after ischemia. Investigative Ophthalmology & Visual Science 53, 2823–2830.Google Scholar
  73. 73.
    Bhatt, L., Groeger, G., McDermott, K., & Cotter, T. G. (2010). Rod and cone photoreceptor cells produce ROS in response to stress in a live retinal explant system. Molecular Vision, 16, 283–293.PubMedGoogle Scholar
  74. 74.
    Yokota, H., Narayanan, S. P., Zhang, W., Liu, H., Rojas, M., Xu, Z., et al. (2011). Neuroprotection from retinal ischemia/reperfusion injury by NOX2 NADPH oxidase deletion. Investigative Ophthalmology and Visual Science, 52(11), 8123–8131.PubMedCrossRefGoogle Scholar
  75. 75.
    Tang, J., & Kern, T. S. (2011). Inflammation in diabetic retinopathy. Progress in Retinal and Eye Research, 30, 343–358.PubMedCrossRefGoogle Scholar
  76. 76.
    Tarr, J. M., Ding, N., Kaul, K., Antonell, A., Perez-Jurado, L. A., & Chibber, R. (2012). Cellular crosstalk between TNF-alpha, NADPH oxidase, PKCbeta2, and C2GNT in human leukocytes. Cellular Signalling, 24, 873–878.PubMedCrossRefGoogle Scholar
  77. 77.
    Chen, P., Guo, A. M., Edwards, P. A., Trick, G., & Scicli, A. G. (2007). Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 293, R1619–R1629.PubMedCrossRefGoogle Scholar
  78. 78.
    Garrido-Urbani, S., Jemelin, S., Deffert, C., Carnesecchi, S., Basset, O., Szyndralewiez, C., et al. (2011). Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARalpha mediated mechanism. PLoS One, 6, e14665.PubMedCrossRefGoogle Scholar
  79. 79.
    Arbiser, J. L., Petros, J., Klafter, R., Govindajaran, B., McLaughlin, E. R., Brown, L. F., et al. (2002). Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proceedings of the National Academy of Sciences of the United States of America, 99, 715–720.PubMedCrossRefGoogle Scholar
  80. 80.
    Saito, Y., Geisen, P., Uppal, A., & Hartnett, M. E. (2007). Inhibition of NAD(P)H oxidase reduces apoptosis and avascular retina in an animal model of retinopathy of prematurity. Molecular Vision, 13, 840–853.PubMedGoogle Scholar
  81. 81.
    Al-Shabrawey, M., Rojas, M., Sanders, T., Behzadian, A., El-Remessy, A., Bartoli, M., et al. (2008). Role of NADPH oxidase in retinal vascular inflammation. Investigative Ophthalmology and Visual Science, 49, 3239–3244.PubMedCrossRefGoogle Scholar
  82. 82.
    Zhang, W., Rojas, M., Lilly, B., Tsai, N. T., Lemtalsi, T., Liou, G. I., et al. (2009). NAD(P)H oxidase-dependent regulation of CCL2 production during retinal inflammation. Investigative Ophthalmology and Visual Science, 50, 3033–3040.PubMedCrossRefGoogle Scholar
  83. 83.
    Tawfik, A., Sanders, T., Kahook, K., AkeeL, S., Elmarakby, A., & Al-Shabrawey, M. (2009). Suppression of retinal peroxisome proliferator-activated receptor gamma in experimental diabetes and oxygen-induced retinopathy: role of NADPH oxidase. Investigative Ophthalmology and Visual Science, 50, 878–884.PubMedCrossRefGoogle Scholar
  84. 84.
    Wilkinson-Berka, J. L., Heine, R., Tan, G., Cooper, M. E., Hatzopoulos, K. M., Fletcher, E. L., et al. (2010). RILLKKMPSV influences the vasculature, neurons and glia, and (pro)renin receptor expression in the retina. Hypertension, 55, 1454–1460.PubMedCrossRefGoogle Scholar
  85. 85.
    Sarlos, S., & Wilkinson-Berka, J. L. (2005). The renin–angiotensin system and the developing retinal vasculature. Investigative Ophthalmology and Visual Science, 46, 1069–1077.PubMedCrossRefGoogle Scholar
  86. 86.
    Wilkinson-Berka, J. L. (2006). Angiotensin and diabetic retinopathy. The International Journal of Biochemistry & Cell Biology, 38, 752–765.CrossRefGoogle Scholar
  87. 87.
    Fukumoto, M., Takai, S., Ishizaki, E., Sugiyama, T., Oku, H., Jin, D., et al. (2008). Involvement of angiotensin II-dependent vascular endothelial growth factor gene expression via NADPH oxidase in the retina in a type 2 diabetic rat model. Current Eye Research, 33, 885–891.PubMedCrossRefGoogle Scholar
  88. 88.
    Li, L., & Renier, G. (2006). Activation of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase by advanced glycation end products links oxidative stress to altered retinal vascular endothelial growth factor expression. Metabolism, 55, 1516–1523.PubMedCrossRefGoogle Scholar
  89. 89.
    Yamagishi, S., Nakamura, K., Matsui, T., Inagaki, Y., Takenaka, K., Jinnouchi, Y., et al. (2006). Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression. Journal of Biological Chemistry, 281(29), 20213–20220.PubMedCrossRefGoogle Scholar
  90. 90.
    Miller, A. G., Tan, G., Binger, K. J., Pickering, R. J., Thomas, M. C., Nagaraj, R. H., et al. (2010). Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function. Diabetes, 59, 3208–3215.PubMedCrossRefGoogle Scholar
  91. 91.
    Barry-Lane, P. A., Patterson, C., Van der Merwe, M., Hu, Z., Holland, S. M., Yeh, E. T. H., et al. (2001). p47phox is required for atherosclerotic lesion progression in ApoE−/− mice. Journal of Clinical Investigation, 108, 1513–1522.PubMedGoogle Scholar
  92. 92.
    Judkins, C. P., Diep, H., Broughton, B. R. S., Mast, A. E., Hooker, E. U., Miller, A. A., et al. (2010). Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE−/− mice. American Journal of Physiology—Heart and Circulatory Physiology, 298, H24–H32.PubMedCrossRefGoogle Scholar
  93. 93.
    Dikalova, A., Clempus, R., Lassegue, B., Cheng, G., Mccoy, J., Dikalov, S., et al. (2005). Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice. Circulation, 112, 2668–2676.PubMedCrossRefGoogle Scholar
  94. 94.
    Shimizu, H., Nakagawa, Y., Murakami, C., Aoki, N., Kim-Mitsuyama, S., & Miyazaki, H. (2010). Protein tyrosine phosphatase PTPepsilonM negatively regulates PDGF beta-receptor signaling induced by high glucose and PDGF in vascular smooth muscle cells. American Journal of Physiology. Cell Physiology, 299(5), C1144–C1145.PubMedCrossRefGoogle Scholar
  95. 95.
    Perrotta, I., Sciangula, A., Perrotta, E., Donato, G., & Cassese, M. (2011). Ultrastructural analysis and electron microscopic localization of Nox4 in healthy and atherosclerotic human aorta. Ultrastructural Pathology, 35(1), 1–6.PubMedCrossRefGoogle Scholar
  96. 96.
    Fenyo, I. M., Florea, I. C., Raicu, M., & Manea, A. (2011). Tyrphostin AG490 reduces NAPDH oxidase activity and expression in the aorta of hypercholesterolemic apolipoprotein E-deficient mice. Vascular Pharmacology, 54(3-6), 100–106.PubMedCrossRefGoogle Scholar
  97. 97.
    Lassègue, B., & Griendling, K. K. (2010). NADPH oxidases: functions and pathologies in the vasculature. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 653–661.PubMedCrossRefGoogle Scholar
  98. 98.
    Matsuno, K., Yamada, H., Iwata, K., Jin, D., Katsuyama, M., Matsuki, M., et al. (2005). Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation, 112, 2677–2685.PubMedCrossRefGoogle Scholar
  99. 99.
    Hart, B. A., Elferink, J. G., & Nibbering, P. H. (1992). Effect of apocynin on the induction of ulcerative lesions in rat skin injected with tubercle bacteria. International Journal of Immunopharmacology, 14(6), 953–961.PubMedCrossRefGoogle Scholar
  100. 100.
    Gatley, S. J., & Sherratt, H. A. S. (1976). The effects of diphenyleneiodonium on mitochondrial reactions. Relation of binding of diphenylene[125I]iodonium to mitochondria to the extent of inhibition of oxygen uptake. Biochemical Journal, 158, 307–315.PubMedGoogle Scholar
  101. 101.
    Aldieri, E., Riganti, C., Polimeni, M., Gazzano, E., Lussiana, C., Campia, I., et al. (2008). Classical inhibitors of NOX NAD(P)H oxidases are not specific. Current Drug Metabolism, 9, 686–696.PubMedCrossRefGoogle Scholar
  102. 102.
    Wind, S., Beuerlein, D., Eucker, T., Müller, H., Scheurer, P., Armitage, M. E., et al. (2010). Comparative pharmacology of chemically distinct NADPH oxidase inhibitors. British Journal of Pharmacology, 161, 885–898.PubMedCrossRefGoogle Scholar
  103. 103.
    Drummond, G. R., Selemidis, S., Griendling, K. K., & Sobey, C. G. (2011). Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nature Reviews. Drug Discovery, 10(6), 453–457.PubMedCrossRefGoogle Scholar
  104. 104.
    Kim, J. A., Neupane, G. P., Lee, E. S., Jeong, B. S., Park, B. C., & Thapa, P. (2011). NADPH oxidase inhibitors: a patent review. Expert Opinion on Therapeutic Patents, 21(8), 1147–1158.PubMedCrossRefGoogle Scholar
  105. 105.
  106. 106.
    Laleu, B., Gaggini, F., Orchard, M., Fioraso-Cartier, I., Cagnon, I., Houngninou-Molango, S., et al. (2010). First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. Journal of Medicinal Chemistry, 53, 7715–7730.PubMedCrossRefGoogle Scholar
  107. 107.
    Page, P., Orchard, M., Fioraso-Cartier, l., Mottironi, B. (2008). Pyrazolo pyridine derivatives as NADPH oxidase inhibitors, Patent WO 2008/113856 A1. Switzerland patent application.Google Scholar
  108. 108.
    Stielow, C., Catar, R. A., Muller, G., Wingler, K., Scheurer, P., Schmidt, H. H. H. W., et al. (2006). Novel Nox inhibitor of oxLDL-induced reactive oxygen species formation in human endothelial cells. Biochemical and Biophysical Research Communications, 344, 200–205.PubMedCrossRefGoogle Scholar
  109. 109.
    Ten Freyhaus, H., Huntgeburth, M., Wingler, K., Schnitker, J., Bäumer, A. T., Vantler, M., et al. (2006). Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. Cardiovascular Research, 71, 331–341.PubMedCrossRefGoogle Scholar
  110. 110.
    Niethammer, P., Grabher, C., Look, A. T., & Mitchison, T. J. (2009). A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature, 459, 996–999.PubMedCrossRefGoogle Scholar
  111. 111.
    Spychalowicz, A., Wilk, G., Sliwa, T., Ludew, D., Guzik, T.J. (2012). Novel therapeutic approaches in limiting oxidative stress and inflammation. Current Pharmaceutical Biotechnology. [Epub ahead of print].Google Scholar
  112. 112.
    Bonner, M.Y., Arbiser, J.L., Targeting, N.A.D.P.H. (2012 May 13). oxidases for the treatment of cancer and inflammation. Cellular and Molecular Life Sciences. [Epub ahead of print].Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Mona Sedeek
    • 1
  • Augusto C. Montezano
    • 1
  • Richard L. Hebert
    • 1
  • Stephen P. Gray
    • 2
  • Elyse Di Marco
    • 2
    • 3
  • Jay C. Jha
    • 2
  • Mark E. Cooper
    • 2
    • 3
    • 4
  • Karin Jandeleit-Dahm
    • 2
    • 3
  • Ernesto L. Schiffrin
    • 5
  • Jennifer L. Wilkinson-Berka
    • 4
  • Rhian M. Touyz
    • 1
    • 6
  1. 1.Ottawa Hospital Research InstituteOttawaCanada
  2. 2.Baker IDI Heart & Diabetes Research InstituteMelbourneAustralia
  3. 3.Department of MedicineMonash UniversityMelbourneAustralia
  4. 4.Department of ImmunologyMonash UniversityMelbourneAustralia
  5. 5.Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General HospitalMcGill UniversityMontrealCanada
  6. 6.Institute for Cardiovascular and Medical sciences, BHF Glasgow Cardiovascular Research CentreUniversity of GlasgowGlasgowUK

Personalised recommendations