Skip to main content
SpringerLink
Log in

Role of Oxidative Stress and Targeted Antioxidant Therapies in Experimental Models of Diabetic Complications

  • Chapter
  • First Online:
Studies on Experimental Models

  • 1300 Accesses

Abstract

Diabetic patients, whether of type 1 or type 2 origin, are at greater risk of developing complications of the vasculature than non-diabetic patients. Macrovascular complications such as diabetes-associated atherosclerosis lead to accelerated and often more advanced lesions than seen in the general population. Microvascular complications such as nephropathy, retinopathy and neuropathy as well as diabetic cardiomyopathy are further complications associated with the diabetic milieu. Understanding the mechanisms leading to and accelerating these complications is a major research initiative of many laboratories. To facilitate these studies, the design and use of appropriate animal models has been central to the study of these diabetic complications. A new and emerging concept underpinning many of these end-organ complications is oxidative stress, particularly of mitochondrial origin, which is understood to play a critical role in the initiation and progression of these diabetic complications. Thus the development of experimental models that specifically delineate the cause and role of ROS in diabetic complications is now becoming a major research area. This chapter focuses on some of the latest oxidative stress-driven experimental models of diabetic complications. Use of the ApoE/GPx1 double-knockout mouse has revealed the importance of antioxidant defense in limiting accelerated diabetes-associated atherosclerosis and diabetic nephropathy, while RAGE knockout mice have shown that oxidative stress is inextricably linked with pathophysiological cell signaling, particularly through RAGE. The use of NOX knockout mice is shedding light on the contribution of the NADPH oxidases to the ROS milieu as well as the contribution of the various isoforms (NOX 1, 2 and 4) to the individual diabetic complications. Furthermore, these models are helping to understand the types of ROS involved and their cellular location, which may help in the specific targeting of these ROS to reduce ROS-mediated pathogenesis. For example, antioxidants that target mitochondrial ROS (location) or ROS such as hydrogen peroxide (specificity) may offer an alternate approach to reduce diabetes-driven oxidative stress. It is only via manipulation of experimental models of diabetes-driven oxidative stress that the contribution of the various ROS will be revealed, and only then that effective treatment regimens can be designed to lessen the effect of oxidative stress on diabetic complications.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–867.

    Article  PubMed  CAS  Google Scholar 

  2. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–820.

    Article  PubMed  CAS  Google Scholar 

  3. Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int Suppl. 2000;77:S26  –30.

    Article  PubMed  CAS  Google Scholar 

  4. Asghar O, Al-Sunni A, Khavandi K, Khavandi A, Withers S, Greenstein A, Heagerty AM, Malik RA. Diabetic cardiomyopathy. Clin Sci (Lond). 2009;116:741–760.

    Article  CAS  Google Scholar 

  5. Calcutt NA, Cooper ME, Kern TS, Schmidt AM. Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat Rev Drug Discov. 2009;8:417–  429.

    Article  PubMed  CAS  Google Scholar 

  6. Zarich SW, Nesto RW. Diabetic cardiomyopathy. Am Heart J. 1989;118:1000–1012.

    Article  PubMed  CAS  Google Scholar 

  7. Adeghate E. Molecular and cellular basis of the aetiology and management of diabetic ­cardiomyopathy: a short review. Mol Cell Biochem. 2004;261:187–191.

    Article  PubMed  CAS  Google Scholar 

  8. Srikanthan P, Hsueh W. Preventing heart failure in patients with diabetes. Med Clin North Am. 2004;88:1237–1256.

    Article  PubMed  CAS  Google Scholar 

  9. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide ­production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–790.

    Article  PubMed  CAS  Google Scholar 

  10. Lee AY, Chung SS. Contributions of polyol pathway to oxidative stress in diabetic cataract. Faseb J. 1999;13:23–30.

    PubMed  CAS  Google Scholar 

  11. Park L, Raman KG, Lee KJ, Lu Y, Ferran LJ, Jr., Chow WS, Stern D, Schmidt AM. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med. 1998;4:1025–1031.

    Article  PubMed  CAS  Google Scholar 

  12. Way KJ, Isshiki K, Suzuma K, Yokota T, Zvagelsky D, Schoen FJ, Sandusky GE, Pechous PA, Vlahos CJ, Wakasaki H, King GL. Expression of connective tissue growth factor is increased in injured myocardium associated with protein kinase C beta2 activation and diabetes. Diabetes. 2002;51:2709–2718.

    Article  PubMed  CAS  Google Scholar 

  13. Sorescu D, Griendling KK. Reactive oxygen species, mitochondria and NADPH oxidases in the development and progression to heart failure. Congestive Heart Failure. 2002;8.

    Google Scholar 

  14. Raha S, McEachern GE, Myint AT, Robinson BH. Superoxides from mitochondrial complex III: The role of manganese superoxide dismutase. Free Radical Biology and Medicine. 2000;29:170  –180.

    Article  PubMed  CAS  Google Scholar 

  15. Guzik TJ, Mussa SM, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, Channon KM. Mechanisms of increased vascular superoxide production in human diabetes mellitus. Circulation. 2002;105:1656–1662.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. De Haan JB, Crack PJ, Flentjar N, Iannello RC, Hertzog P, Kola I. An imbalance in antioxidant defense affects cellular function: the pathophysiological consequences of a reduction in antioxidant defense in the Gpx1 knockout mouse. Redox Report. 2003;8:69  –79.

    Article  PubMed  CAS  Google Scholar 

  18. Lei XG, Cheng WH, McClung JP. Metabolic regulation and function of glutathione peroxidase-1. Annu Rev Nutr. 2007;27:41–  61.

    Article  PubMed  CAS  Google Scholar 

  19. Hsueh W, Abel ED, Breslow JL, Maeda N, Davis RC, Fisher EA, Dansky H, McClain DA, McIndoe R, Wassef MK, Rabadan-Diehl C, Goldberg IJ. Recipes for creating animal models of diabetic cardiovascular disease. Circ Res. 2007;100:1415–1427.

    Article  PubMed  CAS  Google Scholar 

  20. Breyer MD, Bottinger E, Brosius FC, 3rd, Coffman TM, Harris RC, Heilig CW, Sharma K. Mouse models of diabetic nephropathy. J Am Soc Nephrol. 2005;16:27–  45.

    Article  PubMed  Google Scholar 

  21. Allen TJ, Cooper ME, Lan HY. Use of genetic mouse models in the study of diabetic nephropathy. Curr Diab Rep. 2004;4:435–  440.

    Article  PubMed  Google Scholar 

  22. Rees DA, Alcolado JC. Animal models of diabetes mellitus. Diabet Med. 2005;22:359–370.

    Article  PubMed  CAS  Google Scholar 

  23. Pyorala K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev. 1987;3:463–524.

    Article  PubMed  CAS  Google Scholar 

  24. Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O’Leary DH, Genuth S. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med. 2003;348:2294–2303.

    Article  PubMed  Google Scholar 

  25. Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004;63:582–592.

    Article  PubMed  CAS  Google Scholar 

  26. Wendt T, Harja E, Bucciarelli L, Qu W, Lu Y, Rong LL, Jenkins DG, Stein G, Schmidt AM, Yan SF. RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes. Atherosclerosis. 2006;185:70–77.

    Article  PubMed  CAS  Google Scholar 

  27. Candido R, Jandeleit-Dahm KA, Cao Z, Nesteroff SP, Burns WC, Twigg SM, Dilley RJ, Cooper ME, Allen TJ. Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice. Circulation. 2002;106:246–253.

    Article  PubMed  CAS  Google Scholar 

  28. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991;40:405–412.

    Article  PubMed  CAS  Google Scholar 

  29. Inoguchi T, Nawata H. NAD(P)H oxidase activation: a potential target mechanism for diabetic vascular complications, progressive beta-cell dysfunction and metabolic syndrome. Curr Drug Targets. 2005;6:495–501.

    Article  PubMed  CAS  Google Scholar 

  30. Ferroni P, Basili S, Falco A, Davi G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost. 2004;2:1282–1291.

    Article  PubMed  CAS  Google Scholar 

  31. Wang Z, Castresana MR, Newman WH. Reactive oxygen and NF-kappaB in VEGF-induced migration of human vascular smooth muscle cells. Biochem Biophys Res Commun. 2001;285:669–674.

    Article  PubMed  CAS  Google Scholar 

  32. Yang H, Shi M, Richardson A, Vijg J, Guo Z. Attenuation of leukocyte-endothelium interaction by antioxidant enzymes. Free Radic Biol Med. 2003;35:266–276.

    Article  PubMed  CAS  Google Scholar 

  33. Ruperez M, Lorenzo O, Blanco-Colio LM, Esteban V, Egido J, Ruiz-Ortega M. Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis. Circulation. 2003;108:1499–1505.

    Article  PubMed  CAS  Google Scholar 

  34. Schwenke DC, Carew TE. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. I. Focal increases in arterial LDL concentration precede development of fatty streak lesions. Arteriosclerosis. 1989;9:895–907.

    Article  PubMed  CAS  Google Scholar 

  35. Cushing SD, Berliner JA, Valente AJ, Territo MC, Navab M, Parhami F, Gerrity R, Schwartz CJ, Fogelman AM. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA. 1990;87:5134–5138.

    Article  PubMed  CAS  Google Scholar 

  36. Berliner JA, Territo MC, Sevanian A, Ramin S, Kim JA, Bamshad B, Esterson M, Fogelman AM. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990;85:1260–1266.

    Article  PubMed  CAS  Google Scholar 

  37. Forman HJ, Torres M. Redox signaling in macrophages. Mol Aspects Med. 2001;22:189–216.

    Article  PubMed  CAS  Google Scholar 

  38. Fogelman AM, Shechter I, Seager J, Hokom M, Child JS, Edwards PA. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci USA. 1980;77:2214–2218.

    Article  PubMed  CAS  Google Scholar 

  39. Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation. 1999;99:224–229.

    Article  PubMed  CAS  Google Scholar 

  40. Kobayashi S, Inoue N, Azumi H, Seno T, Hirata K, Kawashima S, Hayashi Y, Itoh H, Yokozaki H, Yokoyama M. Expressional changes of the vascular antioxidant system in atherosclerotic coronary arteries. J Atheroscler Thromb. 2002;9:184–190.

    Article  PubMed  CAS  Google Scholar 

  41. t Hoen PA, Van der Lans CA, Van Eck M, Bijsterbosch MK, Van Berkel TJ, Twisk J. Aorta of ApoE-deficient mice responds to atherogenic stimuli by a prelesional increase and subsequent decrease in the expression of antioxidant enzymes. Circ Res. 2003;93:262–269.

    Google Scholar 

  42. Yang H, Roberts LJ, Shi MJ, Zhou LC, Ballard BR, Richardson A, Guo ZM. Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E. Circ Res. 2004;95:1075–1081.

    Article  PubMed  CAS  Google Scholar 

  43. Blankenberg S, Rupprecht HJ, Bickel C, Torzewski M, Hafner G, Tiret L, Smieja M, Cambien F, Meyer J, Lackner KJ. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N Engl J Med. 2003;349:1605–1613.

    Article  PubMed  CAS  Google Scholar 

  44. Schnabel R, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Torzewski M, Lubos E, Bickel C, Cambien F, Tiret L, Munzel T, Blankenberg S. Glutathione peroxidase-1 and homocysteine for cardiovascular risk prediction: results from the AtheroGene study. J Am Coll Cardiol. 2005;45:1631–1637.

    Article  PubMed  CAS  Google Scholar 

  45. Winter JP, Gong Y, Grant PJ, Wild CP. Glutathione peroxidase 1 genotype is associated with an increased risk of coronary artery disease. Coron Artery Dis. 2003;14:149–153.

    Article  PubMed  Google Scholar 

  46. Hamanishi T, Furuta H, Kato H, Doi A, Tamai M, Shimomura H, Sakagashira S, Nishi M, Sasaki H, Sanke T, Nanjo K. Functional variants in the glutathione peroxidase-1 (GPx-1) gene are associated with increased intima-media thickness of carotid arteries and risk of macrovascular diseases inJapanese type 2 diabetic patients. Diabetes. 2004;53:2455–2460.

    Article  PubMed  CAS  Google Scholar 

  47. Nemoto M, Nishimura R, Sasaki T, Hiki Y, Miyashita Y, Nishioka M, Fujimoto K, Sakuma T, Ohashi T, Fukuda K, Eto Y, Tajima N. Genetic association of glutathione peroxidase-1 with coronary artery calcification in type 2 diabetes: a case control study with multi-slice computed tomography. Cardiovasc Diabetol. 2007;6:23.

    Article  PubMed  CAS  Google Scholar 

  48. Brigelius-Flohe R, Banning A, Schnurr K. Selenium-dependent enzymes in endothelial cell function. Antioxid Redox Signal. 2003;5:205–215.

    Article  PubMed  CAS  Google Scholar 

  49. Sies H, Sharov VS, Klotz LO, Briviba K. Glutathione peroxidase protects against ­peroxynitrite-mediated oxidations. A new function for selenoproteins as peroxynitrite reductase. J Biol Chem. 1997;272:27812–27817.

    Article  PubMed  CAS  Google Scholar 

  50. De Haan J.B, Bladier C, Griffiths P, Kelner M, O’Shea RD, Cheung NS, Bronson RT, Silvestro MJ, Wild S, Zheng SS, Beart PM, Hertzog P, Kola I. Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide. The American Society of Biochemistry and Molecular Biology. 1998;273:22528–22536.

    Google Scholar 

  51. Esposito LA, Kokoszka JE, Waymire KG, Cottrell B, MacGregor GR, Wallace DC. Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene. Free Radic Biol Med. 2000;28:754–766.

    Article  PubMed  CAS  Google Scholar 

  52. Yoshida T, Maulik N, Engelman RM, Ho Y, Magnenat J, Rousou JA, Flack JE, Deaton D, Das DK. Glutathione peroxidase knockout mice are susceptible to myocardial ischemia reperfusion injury. Circulation. 1997;96:II–216–II–220.

    Google Scholar 

  53. Rosenblat M, Aviram M. Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies. Free Radic Biol Med. 1998;24:305–317.

    Article  PubMed  CAS  Google Scholar 

  54. Crack PJ, Taylor JM, Flentjar NJ, de Haan J, Hertzog P, Iannello RC, Kola I. Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury. J Neurochem. 2001;78:1389–1399.

    Article  PubMed  CAS  Google Scholar 

  55. Flentjar NJ, Crack PJ, Boyd R, Malin M, de Haan JB, Hertzog P, Kola I, Iannello R. Mice lacking glutathione peroxidase-1 activity show increased TUNEL staining and an accelerated inflammatory response in brain following a cold-induced injury. Exp Neurol. 2002;177:9–20.

    Article  PubMed  CAS  Google Scholar 

  56. de Haan JB, Witting PK, Stefanovic N, Pete J, Daskalakis M, Kola I, Stocker R, Smolich JJ. Deficiency in the antioxidant enzyme glutathione peroxidase-1 (Gpx1) does not increase atherosclerosis in C57BL/J6 mice fed a high fat diet. J Lipid Res. 2006.

    Google Scholar 

  57. Lewis P, Stefanovic N, Pete J, Calkin AC, Giunti S, Thallas-Bonke V, Jandeleit-Dahm KA, Allen TJ, Kola I, Cooper ME, de Haan JB. Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. Circulation. 2007;115:2178–2187.

    Article  PubMed  CAS  Google Scholar 

  58. Torzewski M, Ochsenhirt V, Kleschyov AL, Oelze M, Daiber A, Li H, Rossmann H, Tsimikas S, Reifenberg K, Cheng F, Lehr HA, Blankenberg S, Forstermann U, Munzel T, Lackner KJ. Deficiency of glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2007;27:850–857.

    Article  PubMed  CAS  Google Scholar 

  59. Harja E, Bu DX, Hudson BI, Chang JS, Shen X, Hallam K, Kalea AZ, Lu Y, Rosario RH, Oruganti S, Nikolla Z, Belov D, Lalla E, Ramasamy R, Yan SF, Schmidt AM. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice. J Clin Invest. 2008;118:183–194.

    Article  PubMed  CAS  Google Scholar 

  60. Paigen B, Ishida BY, Verstuyft J, Winters RB, Albee D. Atherosclerosis susceptibility ­differences among progenitors of recombinant inbred strains of mice. Arteriosclerosis. 1990;10:316–323.

    Article  PubMed  CAS  Google Scholar 

  61. Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis. 1987;68:231–240.

    Article  PubMed  CAS  Google Scholar 

  62. Paigen B, Plump AS, Rubin EM. The mouse as a model for human cardiovascular disease and hyperlipidemia. Curr Opin Lipidol. 1994;5:258–264.

    Article  PubMed  CAS  Google Scholar 

  63. Kolovou G, Anagnostopoulou K, Mikhailidis DP, Cokkinos DV. Apolipoprotein E knockout models. Curr Pharm Des. 2008;14:338–351.

    Article  PubMed  CAS  Google Scholar 

  64. Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest. 1994;93:1885–1893.

    Article  PubMed  CAS  Google Scholar 

  65. Leto TL, Geiszt M. Role of Nox family NADPH oxidases in host defense. Antioxid Redox Signal. 2006;8:1549–1561.

    Article  PubMed  CAS  Google Scholar 

  66. Geiszt M. NADPH oxidases: new kids on the block. Cardiovasc Res. 2006;71:289–299.

    Article  PubMed  CAS  Google Scholar 

  67. Gorin Y, Block K, Hernandez J, Bhandari B, Wagner B, Barnes JL, Abboud HE. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J Biol Chem. 2005;280:39616–39626.

    Article  PubMed  CAS  Google Scholar 

  68. Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK. Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004;24:677–683.

    Article  PubMed  CAS  Google Scholar 

  69. Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol. 2003;285:R277–297.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  71. Ellmark SH, Dusting GJ, Fui MN, Guzzo-Pernell N, Drummond GR. The contribution of Nox4 to NADPH oxidase activity in mouse vascular smooth muscle. Cardiovasc Res. 2005;65:495–504.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  73. Dikalov SI, Dikalova AE, Bikineyeva AT, Schmidt HH, Harrison DG, Griendling KK. Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production. Free Radic Biol Med. 2008;45:1340–1351.

    Article  PubMed  CAS  Google Scholar 

  74. Matsuno K, Yamada H, Iwata K, Jin D, Katsuyama M, Matsuki M, Takai S, Yamanishi K, Miyazaki M, Matsubara H, Yabe-Nishimura C. Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation. 2005;112:2677–2685.

    Article  PubMed  CAS  Google Scholar 

  75. Kirk EA, Dinauer MC, Rosen H, Chait A, Heinecke JW, LeBoeuf RC. Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2000;20:1529–1535.

    Article  PubMed  CAS  Google Scholar 

  76. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol. 2004;24:12–22.

    Article  PubMed  CAS  Google Scholar 

  77. El-Benna J, Dang PM, Gougerot-Pocidalo MA, Marie JC, Braut-Boucher F. p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases. Exp Mol Med. 2009;41:217–225.

    Article  PubMed  CAS  Google Scholar 

  78. Hsich E, Segal BH, Pagano PJ, Rey FE, Paigen B, Deleonardis J, Hoyt RF, Holland SM, Finkel T. Vascular effects following homozygous disruption of p47(phox): An essential component of NADPH oxidase. Circulation. 2000;101:1234–1236.

    Article  PubMed  CAS  Google Scholar 

  79. Barry-Lane PA, Patterson C, van der Merwe M, Hu Z, Holland SM, Yeh ET, Runge MS. p47phox is required for atherosclerotic lesion progression in ApoE(-/-) mice. J Clin Invest. 2001;108:1513–1522.

    PubMed  CAS  Google Scholar 

  80. Judkins CP, Diep H, Broughton BR, Mast AE, Hooker EU, Miller AA, Selemidis S, Dusting GJ, Sobey CG, Drummond GR. Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability and early atherosclerotic plaque formation in ApoE-/- mice. Am J Physiol Heart Circ Physiol. 2009.

    Google Scholar 

  81. Guzik TJ, Chen W, Gongora MC, Guzik B, Lob HE, Mangalat D, Hoch N, Dikalov S, Rudzinski P, Kapelak B, Sadowski J, Harrison DG. Calcium-dependent NOX5 nicotinamide adenine dinucleotide phosphate oxidase contributes to vascular oxidative stress in human coronary artery disease. J Am Coll Cardiol. 2008;52:1803–1809.

    Article  PubMed  CAS  Google Scholar 

  82. Schulz E, Munzel T. NOX5, a new “radical” player in human atherosclerosis? J Am Coll Cardiol. 2008;52:1810–1812.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  85. Yamagishi S, Nakamura K, Matsui T, Ueda S, Fukami K, Okuda S. Agents that block advanced glycation end product (AGE)-RAGE (receptor for AGEs)-oxidative stress system: a novel therapeutic strategy for diabetic vascular complications. Expert Opin Investig Drugs. 2008;17:983–996.

    Article  PubMed  CAS  Google Scholar 

  86. Yamagishi S, Ueda S, Matsui T, Nakamura K, Okuda S. Role of advanced glycation end products (AGEs) and oxidative stress in diabetic retinopathy. Curr Pharm Des. 2008;14:962–968.

    Article  PubMed  CAS  Google Scholar 

  87. Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, Pinsky D, Stern D. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994;269:9889–9897.

    PubMed  CAS  Google Scholar 

  88. Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb. 1994;14:1521–1528.

    Article  PubMed  CAS  Google Scholar 

  89. Sun L, Ishida T, Yasuda T, Kojima Y, Honjo T, Yamamoto Y, Yamamoto H, Ishibashi S, Hirata K, Hayashi Y. RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice. Cardiovasc Res. 2009;82:371–381.

    Article  PubMed  CAS  Google Scholar 

  90. Torreggiani M, Liu H, Wu J, Zheng F, Cai W, Striker G, Vlassara H. Advanced glycation end product receptor-1 transgenic mice are resistant to inflammation, oxidative stress, and post-injury intimal hyperplasia. Am J Pathol. 2009;175:1722–1732.

    Article  PubMed  CAS  Google Scholar 

  91. Soro-Paavonen A, Watson AM, Li J, Paavonen K, Koitka A, Calkin AC, Barit D, Coughlan MT, Drew BG, Lancaster GI, Thomas M, Forbes JM, Nawroth PP, Bierhaus A, Cooper ME, Jandeleit-Dahm KA. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes. 2008;57:2461–2469.

    Article  PubMed  CAS  Google Scholar 

  92. Cooper ME. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet. 1998;352:213–219.

    Article  PubMed  CAS  Google Scholar 

  93. Keane WF, Zhang Z, Lyle PA, Cooper ME, de Zeeuw D, Grunfeld JP, Lash JP, McGill JB, Mitch WE, Remuzzi G, Shahinfar S, Snapinn SM, Toto R, Brenner BM. Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study. Clin J Am Soc Nephrol. 2006;1:761–767.

    Article  PubMed  Google Scholar 

  94. Barit D, Cooper ME. Diabetic patients and kidney protection: an attainable target. J Hypertens. 2008;26 Suppl 2:S3–7.

    Article  CAS  Google Scholar 

  95. Diamond JR. The role of reactive oxygen species in animal models of glomerular disease. Am J Kidney Dis. 1992;19:292–300.

    PubMed  CAS  Google Scholar 

  96. Tan AL, Forbes JM, Cooper ME. AGE, RAGE, and ROS in diabetic nephropathy. Semin Nephrol. 2007;27:130–143.

    Article  PubMed  CAS  Google Scholar 

  97. Fukami K, Yamagishi S, Ueda S, Okuda S. Role of AGEs in diabetic nephropathy. Curr Pharm Des. 2008;14:946–952.

    Article  PubMed  CAS  Google Scholar 

  98. Lee EA, Seo JY, Jiang Z, Yu MR, Kwon MK, Ha H, Lee HB. Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 up-regulation in mesangial cells and in diabetic kidney. Kidney Int. 2005;67:1762–1771.

    Article  PubMed  CAS  Google Scholar 

  99. Guo B, Inoki K, Isono M, Mori H, Kanasaki K, Sugimoto T, Akiba S, Sato T, Yang B, Kikkawa R, Kashiwagi A, Haneda M, Koya D. MAPK/AP-1-dependent regulation of PAI-1 gene expression by TGF-beta in rat mesangial cells. Kidney Int. 2005;68:972–984.

    Article  PubMed  CAS  Google Scholar 

  100. Sindhu RK, Ehdaie A, Farmand F, Dhaliwal KK, Nguyen T, Zhan CD, Roberts CK, Vaziri ND. Expression of catalase and glutathione peroxidase in renal insufficiency. Biochim Biophys Acta. 2005;1743:86–92.

    Article  PubMed  CAS  Google Scholar 

  101. Reddi AS, Bollineni JS. Selenium-deficient diet induces renal oxidative stress and injury via TGF-beta1 in normal and diabetic rats. Kidney Int. 2001;59:1342–1353.

    Article  PubMed  CAS  Google Scholar 

  102. de Haan JB, Stefanovic N, Nikolic-Paterson D, Scurr LL, Croft KD, Mori TA, Hertzog P, Kola I, Atkins RC, Tesch GH. Kidney expression of glutathione peroxidase-1 is not protective against streptozotocin-induced diabetic nephropathy. Am J Physiol Renal Physiol. 2005;289:F544–551.

    Article  PubMed  CAS  Google Scholar 

  103. Hirano T. Lipoprotein abnormalities in diabetic nephropathy. Kidney Int Suppl. 1999;71:S22–24.

    Article  PubMed  CAS  Google Scholar 

  104. Jenkins AJ, Lyons TJ, Zheng D, Otvos JD, Lackland DT, McGee D, Garvey WT, Klein RL. Lipoproteins in the DCCT/EDIC cohort: associations with diabetic nephropathy. Kidney Int. 2003;64:817–828.

    Article  PubMed  CAS  Google Scholar 

  105. Lassila M, Seah KK, Allen TJ, Thallas V, Thomas MC, Candido R, Burns WC, Forbes JM, Calkin AC, Cooper ME, Jandeleit-Dahm KA. Accelerated nephropathy in diabetic apolipoprotein e-knockout mouse: role of advanced glycation end products. J Am Soc Nephrol. 2004;15:2125–2138.

    Article  PubMed  CAS  Google Scholar 

  106. Yoshioka K, Takemura T, Tohda M, Akano N, Miyamoto H, Ooshima A, Maki S. Glomerular localization of type III collagen in human kidney disease. Kidney Int. 1989;35:1203  –1211.

    Article  PubMed  CAS  Google Scholar 

  107. Horie K, Miyata T, Maeda K, Miyata S, Sugiyama S, Sakai H, van Ypersole de Strihou C, Monnier VM, Witztum JL, Kurokawa K. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest. 1997;100:2995–3004.

    Google Scholar 

  108. Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int. 1999;56:1627–1637.

    Article  PubMed  CAS  Google Scholar 

  109. Inoguchi T, Tsubouchi H, Etoh T, Kakimoto M, Sonta T, Utsumi H, Sumimoto H, Yu HY, Sonoda N, Inuo M, Sato N, Sekiguchi N, Kobayashi K, Nawata H. A possible target of antioxidative therapy for diabetic vascular complications-vascular NAD(P)H oxidase. Curr Med Chem. 2003;10:1759–1764.

    Article  PubMed  CAS  Google Scholar 

  110. Gill PS, Wilcox CS. NADPH oxidases in the kidney. Antioxid Redox Signal. 2006;8:1597–1607.

    Article  PubMed  CAS  Google Scholar 

  111. Kitada M, Koya D, Sugimoto T, Isono M, Araki S, Kashiwagi A, Haneda M. Translocation of glomerular p47phox and p67phox by protein kinase C-beta activation is required for ­oxidative stress in diabetic nephropathy. Diabetes. 2003;52:2603–2614.

    Article  PubMed  CAS  Google Scholar 

  112. Etoh T, Inoguchi T, Kakimoto M, Sonoda N, Kobayashi K, Kuroda J, Sumimoto H, Nawata H. Increased expression of NAD(P)H oxidase subunits, NOX4 and p22phox, in the kidney of streptozotocin-induced diabetic rats and its reversibity by interventive insulin treatment. Diabetologia. 2003;46:1428–1437.

    Article  PubMed  CAS  Google Scholar 

  113. Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int. 2002;61:186–194.

    Article  PubMed  CAS  Google Scholar 

  114. Grob ML, Heib N, Weckbach M, Hansen A, El-Shakmak A, Szabo A, Munter K, Ritz E, Amann K. ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes. Diabetologia. 2004;47:316–324.

    Article  CAS  Google Scholar 

  115. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P. Myocardial cell death in human diabetes. Circulation Research. 2000;87:1123–1132.

    Article  PubMed  CAS  Google Scholar 

  116. Devereux RB, Roman MJ, Paranicas M, O’Grady MJ, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER, Howard BV. Impact of diabetes on cardiac structure and function: The strong heart study. Circulation. 2000;101:2271–2276.

    Article  PubMed  CAS  Google Scholar 

  117. Doi K, Swada F, Toda G, Yamachika S, Seto S, Urata Y, Ihara Y, Sakata N, Taniguchi N, Kondo T, Yano K. Alteration of antioxidants during the progression of heart disease in streptozotocin-induced diabetic rats. Free Radical Respiration. 2001;34:251–261.

    Google Scholar 

  118. Rubler S, Dlugash J, Yuceoglu YZ, Branwood AR, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. The American Journal of Cardiology. 1972;30:595–602.

    Article  PubMed  CAS  Google Scholar 

  119. Tschope C, Walther T, Koniger J, Spillmann F, Westermann D, Escher F, Pauschinger M, Pesquero JB, Bader M, Scultheiss H, Noutsias M. Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. FASEB. 2004;18:828–835.

    Article  CAS  Google Scholar 

  120. Mellor KM, Ritchie RH, Delbridge LM. Reactive Oxygen Species and Insulin Resistant Cardiomyopathy. Clin Exp Pharmacol Physiol. 2009.

    Google Scholar 

  121. Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care. 1996;19:257–264.

    Article  PubMed  CAS  Google Scholar 

  122. Marra G, Cotroneo P, Pitocco D, Manto A, Di Leo M.A.S, Ruotolo V, Caputo S, Giardina B, Ghirlanda G, Sanini SA. Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated type I diabetes. Diabetes Care. 2002;25:370–375.

    Article  PubMed  Google Scholar 

  123. Serpillon S, Floyd BC, Gupte RS, George S, Kozicky M, Neito V, Recchia F, Stanley W, Wolin MS, Gupte SA. Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. Am J Physiol Heart Circ Physiol. 2009;297:H153–162.

    Article  PubMed  CAS  Google Scholar 

  124. Ye G, Metreveli NS, Ren J, Epstein PN. Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes. 2003;52:777–783.

    Article  PubMed  CAS  Google Scholar 

  125. Dhalla AK, Hill MF, Singal PK. Role of oxidative stress in transition of hypertrophy to heart failure. Journal of American College Cardiology. 1996;28:506–514.

    Article  CAS  Google Scholar 

  126. Liang Q, Carlson EC, Donthi RV, Kralik PM, Shen X, Epstein P. Overexpression of Metallothionein reduces diabetic cardiomyopathy. Diabetes. 2002;51:174–181.

    Article  PubMed  CAS  Google Scholar 

  127. Shiomi T, Tsutsui H, Matsusaka H, Murakami K, Hayashidani S, Ikesuchi M, Wen J, Kubota T, Utsumi H, Takeshira A. Overexpression of glutathione peroxidase prevents left ventricular remodelling and failure after myocardial infarction in mice. Circulation. 2004;9:544–549.

    Article  CAS  Google Scholar 

  128. Maulik N, Yoshida T, Das DK. Regulation of cardiomyocyte apoptosis in ischemic reperfused mouse heart by glutathione peroxidase. Molecular and Cellular Biochemistry. 1999;196:13–21.

    Article  PubMed  CAS  Google Scholar 

  129. Ye Gang, Metreveli NS, Donathi RV, Xia S, Xu M, Carlson EC, Epstein PN. Catalase ­protects cardiomyocyte function in models of type I and type 2 Diabetes. Diabetes. 2004;53:1336–1343.

    Google Scholar 

  130. Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nature Genetics. 1995;11:376–380.

    Article  PubMed  CAS  Google Scholar 

  131. Jones SP, Hoffmeyer MR, Sharp BR, Ho YS, Lefer DJ. Role of intracellular antioxidant enzymes after in vivo myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2003;284:H277–282.

    PubMed  CAS  Google Scholar 

  132. Ghosh S, Qi D, An D, Pulinikunnil T A, Brahani A, Kuo K, Wambolt RB, Allard M, Innis SM, Rodrigues B. Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA. American Journal of Physiology Heart Circulation Physiology. 2004;287:H2518–2527.

    Article  CAS  Google Scholar 

  133. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium; mitochondrial cytochrome c-mediated caspase-3 activation pathway. Diabetes. 2002;51:1938–1948.

    Article  PubMed  CAS  Google Scholar 

  134. Song Y, Du Y, Prabhu SD, Epstein PN. Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility. Rev Diabet Stud. 2007;4:159–168.

    Article  PubMed  Google Scholar 

  135. Zhang GX, Lu XM, Kimura S, Nishiyama A. Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation. Cardiovasc Res. 2007;76:204–212.

    Article  PubMed  CAS  Google Scholar 

  136. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM. Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation. 2002;105:293–296.

    Article  PubMed  CAS  Google Scholar 

  137. Kajstura J, Fiordaliso F, Andreoli AM, Li B, Chimenti S, Medow MS, Limana F, Nadal-Ginard B, Leri A, Anversa P. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes. 2001;50:1414–1424.

    Article  PubMed  CAS  Google Scholar 

  138. 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. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001;88:E14–22.

    Article  PubMed  CAS  Google Scholar 

  139. Coughlan MT, Thorburn DR, Penfold SA, Laskowski A, Harcourt BE, Sourris KC, Tan AL, Fukami K, Thallas-Bonke V, Nawroth PP, Brownlee M, Bierhaus A, Cooper ME, Forbes JM. RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J Am Soc Nephrol. 2009;20:742–752.

    Article  PubMed  CAS  Google Scholar 

  140. Kaul N, Siveski-Iliskovic N, Thomas TP, Hill M, Khaper N, Singal PK. Probucol improves antioxidant activity and modulates development of diabetic cardiomyopathy. Nutrition. 1995;11:551–554.

    PubMed  CAS  Google Scholar 

  141. Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. Jama. 2005;294:56–65.

    Article  PubMed  CAS  Google Scholar 

  142. McQueen MJ, Lonn E, Gerstein HC, Bosch J, Yusuf S. The HOPE (Heart Outcomes Prevention Evaluation) Study and its consequences. Scand J Clin Lab Invest Suppl. 2005;240:143–156.

    Article  PubMed  CAS  Google Scholar 

  143. Marchioli R, Levantesi G, Macchia A, Marfisi RM, Nicolosi GL, Tavazzi L, Tognoni G, Valagussa F. Vitamin E increases the risk of developing heart failure after myocardial ­infarction: Results from the GISSI-Prevenzione trial. J Cardiovasc Med (Hagerstown). 2006;7:347–350.

    Article  Google Scholar 

  144. Sheikh-Ali M, Chehade JM, Mooradian AD. The Antioxidant Paradox in Diabetes Mellitus. Am J Ther. 2009.

    Google Scholar 

  145. Chew P, Yuen DY, Koh P, Stefanovic N, Febbraio MA, Kola I, Cooper ME, de Haan JB. Site-specific antiatherogenic effect of the antioxidant ebselen in the diabetic apolipoprotein E-deficient mouse. Arterioscler Thromb Vasc Biol. 2009;29:823–830.

    Article  PubMed  CAS  Google Scholar 

  146. Sies H, Masumoto H. Ebselen as a glutathione peroxidase mimic and as a scavenger of ­peroxynitrite. Adv Pharmacol. 1997;38:229–246.

    Article  PubMed  CAS  Google Scholar 

  147. Muller A, Cadenas E, Graf P, Sies H. A novel biologically active seleno-organic ­compound  – I. Glutathione peroxidase-like activity in vitro and antioxidant capacity of PZ 51 (Ebselen). Biochem Pharmacol. 1984;33:3235–3239.

    Article  PubMed  CAS  Google Scholar 

  148. Parnham MJ, Leyck S, Kuhl P, Schalkwijk J, van den Berg WB. Ebselen: a new approach to the inhibition of peroxide-dependent inflammation. Int J Tissue React. 1987;9:45–50.

    PubMed  CAS  Google Scholar 

  149. Maiorino M, Roveri A, Coassin M, Ursini F. Kinetic mechanism and substrate specificity of glutathione peroxidase activity of ebselen (PZ51). Biochem Pharmacol. 1988;37:2267–2271.

    Article  PubMed  CAS  Google Scholar 

  150. Safayhi H, Tiegs G, Wendel A. A novel biologically active seleno-organic compound  – V. Inhibition by ebselen (PZ 51) of rat peritoneal neutrophil lipoxygenase. Biochem Pharmacol. 1985;34:2691–2694.

    Article  PubMed  CAS  Google Scholar 

  151. Yang CF, Shen HM, Ong CN. Protective effect of ebselen against hydrogen peroxide-induced cytotoxicity and DNA damage in HepG2 cells. Biochem Pharmacol. 1999;57:273–279.

    Article  PubMed  CAS  Google Scholar 

  152. Li J, Chen JJ, Zhang F, Zhang C. Ebselen protection against hydrogen peroxide-induced cytotoxicity and DNA damage in HL-60 cells. Acta Pharmacol Sin. 2000;21:455–459.

    PubMed  CAS  Google Scholar 

  153. Yoshizumi M, Fujita Y, Izawa Y, Suzaki Y, Kyaw M, Ali N, Tsuchiya K, Kagami S, Yano S, Sone S, Tamaki T. Ebselen inhibits tumor necrosis factor-alpha-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. Exp Cell Res. 2004;292:1–10.

    Article  PubMed  CAS  Google Scholar 

  154. Ali N, Yoshizumi M, Tsuchiya K, Kyaw M, Fujita Y, Izawa Y, Abe S, Kanematsu Y, Kagami S, Tamaki T. Ebselen inhibits p38 mitogen-activated protein kinase-mediated endothelial cell death by hydrogen peroxide. Eur J Pharmacol. 2004;485:127–135.

    Article  PubMed  CAS  Google Scholar 

  155. Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke. 1998;29:12–17.

    Article  PubMed  CAS  Google Scholar 

  156. Sui H, Wang W, Wang PH, Liu LS. Effect of glutathione peroxidase mimic ebselen (PZ51) on endothelium and vascular structure of stroke-prone spontaneously hypertensive rats. Blood Press. 2005;14:366–372.

    Article  PubMed  CAS  Google Scholar 

  157. Davis MT, Bartfay WJ. Ebselen decreases oxygen free radical production and iron concentrations in the hearts of chronically iron-overloaded mice. Biol Res Nurs. 2004;6:37–45.

    Article  PubMed  Google Scholar 

  158. Brodsky SV, Gealekman O, Chen J, Zhang F, Togashi N, Crabtree M, Gross SS, Nasjletti A, Goligorsky MS. Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen. Circ Res. 2004;94:377–384.

    Article  PubMed  CAS  Google Scholar 

  159. Khatri JJ, Johnson C, Magid R, Lessner SM, Laude KM, Dikalov SI, Harrison DG, Sung HJ, Rong Y, Galis ZS. Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma. Circulation. 2004;109:520–525.

    Article  PubMed  CAS  Google Scholar 

  160. Ogawa A, Yoshimoto T, Kikuchi H, Sano K, Saito I, Yamaguchi T, Yasuhara H. Ebselen in acute middle cerebral artery occlusion: a placebo-controlled, double-blind clinical trial. Cerebrovasc Dis. 1999;9:112–118.

    Article  PubMed  CAS  Google Scholar 

  161. Witting PK, Pettersson K, Letters J, Stocker R. Site-specific antiatherogenic effect of probucol in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2000;20:E26–33.

    Article  PubMed  CAS  Google Scholar 

  162. Schmid JA, Birbach A. IkappaB kinase beta (IKKbeta/IKK2/IKBKB)  –a key molecule in signaling to the transcription factor NF-kappaB. Cytokine Growth Factor Rev. 2008;19:157–165.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  164. Hacker H, Karin M. Regulation and function of IKK and IKK-related kinases. Sci STKE. 2006;2006:re13.

    Google Scholar 

  165. Yuen DY, Dwyer RM, Matthews VB, Zhang L, Drew BG, Neill B, Kingwell BA, Clark MG, Rattigan S, Febbraio MA. Interleukin-6 attenuates insulin-mediated increases in endothelial cell signaling but augments skeletal muscle insulin action via differential effects on tumor necrosis factor-alpha expression. Diabetes. 2009;58:1086–1095.

    Article  PubMed  CAS  Google Scholar 

  166. Sharma V, Tewari R, Sk UH, Joseph C, Sen E. Ebselen sensitizes glioblastoma cells to Tumor Necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formation of death inducing ­signaling complex. Int J Cancer. 2008;123:2204–2212.

    Article  PubMed  CAS  Google Scholar 

  167. Tewari R, Sharma V, Koul N, Ghosh A, Joseph C, Hossain Sk U, Sen E. Ebselen abrogates TNFalpha induced pro-inflammatory response in glioblastoma. Mol Oncol. 2009;3:77–  83.

    Google Scholar 

  168. Min W, Pober JS. TNF initiates E-selectin transcription in human endothelial cells through parallel TRAF-NF-kappa B and TRAF-RAC/CDC42-JNK-c-Jun/ATF2 pathways. J Immunol. 1997;159:3508–3518.

    PubMed  CAS  Google Scholar 

  169. Read MA, Whitley MZ, Gupta S, Pierce JW, Best J, Davis RJ, Collins T. Tumor necrosis factor alpha-induced E-selectin expression is activated by the nuclear factor-kappaB and c-JUN N-terminal kinase/p38 mitogen-activated protein kinase pathways. J Biol Chem. 1997;272:2753–2761.

    Article  PubMed  CAS  Google Scholar 

  170. Yoshizumi M, Kogame T, Suzaki Y, Fujita Y, Kyaw M, Kirima K, Ishizawa K, Tsuchiya K, Kagami S, Tamaki T. Ebselen attenuates oxidative stress-induced apoptosis via the inhibition of the c-Jun N-terminal kinase and activator protein-1 signaling pathway in PC12 cells. Br J Pharmacol. 2002;136:1023–1032.

    Article  PubMed  CAS  Google Scholar 

  171. Jauslin ML, Wirth T, Meier T, Schoumacher F. A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy. Hum Mol Genet. 2002;11:3055–3063.

    Article  PubMed  CAS  Google Scholar 

  172. Dhanasekaran A, Kotamraju S, Karunakaran C, Kalivendi SV, Thomas S, Joseph J, Kalyanaraman B. Mitochondria superoxide dismutase mimetic inhibits peroxide-induced oxidative damage and apoptosis: role of mitochondrial superoxide. Free Radic Biol Med. 2005;39:567–583.

    Article  PubMed  CAS  Google Scholar 

  173. Dhanasekaran A, Kotamraju S, Kalivendi SV, Matsunaga T, Shang T, Keszler A, Joseph J, Kalyanaraman B. Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem. 2004;279:37575–37587.

    Article  PubMed  CAS  Google Scholar 

  174. Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, Sammut IA. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. Faseb J. 2005;19:1088–1095.

    Article  PubMed  CAS  Google Scholar 

  175. Ross MF, Kelso GF, Blaikie FH, James AM, Cocheme HM, Filipovska A, Da Ros T, Hurd TR, Smith RA, Murphy MP. Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry (Mosc). 2005;70:222–230.

    Article  CAS  Google Scholar 

  176. Subramanian S, Kalyanaraman B, Migrino RQ. Mitochondrially Targeted Antioxidants for the Treatment of Cardiovascular Diseases. Recent Pat Cardiovasc Drug Discov. 2009.

    Google Scholar 

  177. Victor VM, Rocha M. Targeting antioxidants to mitochondria: a potential new therapeutic strategy for cardiovascular diseases. Curr Pharm Des. 2007;13:845  –  863.

    Article  PubMed  CAS  Google Scholar 

  178. Smith RA, Porteous CM, Coulter CV, Murphy MP. Selective targeting of an antioxidant to mitochondria. Eur J Biochem. 1999;263:709–716.

    Article  PubMed  CAS  Google Scholar 

  179. Kohler JJ, Cucoranu I, Fields E, Green E, He S, Hoying A, Russ R, Abuin A, Johnson D, Hosseini SH, Raper CM, Lewis W. Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy. Lab Invest. 2009;89:782–790.

    Article  PubMed  CAS  Google Scholar 

  180. Filipovska A, Kelso GF, Brown SE, Beer SM, Smith RA, Murphy MP. Synthesis and characterization of a triphenylphosphonium-conjugated peroxidase mimetic. Insights into the interaction of ebselen with mitochondria. J Biol Chem. 2005;280:24113–24126.

    Article  PubMed  CAS  Google Scholar 

  181. Kakehi T, Yabe-Nishimura C. NOX enzymes and diabetic complications. Semin Immunopathol. 2008;30:301–314.

    Article  PubMed  CAS  Google Scholar 

  182. Xu M, Dai DZ, Dai Y. Normalizing NADPH oxidase contributes to attenuating diabetic nephropathy by the dual endothelin receptor antagonist CPU0213 in rats. Am J Nephrol. 2009;29:252–256.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  184. Williams HC, Griendling KK. NADPH oxidase inhibitors: new antihypertensive agents? J Cardiovasc Pharmacol. 2007;50:9–16.

    Article  PubMed  CAS  Google Scholar 

  185. Nam SM, Lee MY, Koh JH, Park JH, Shin JY, Shin YG, Koh SB, Lee EY, Chung CH. Effects of NADPH oxidase inhibitor on diabetic nephropathy in OLETF rats: the role of reducing oxidative stress in its protective property. Diabetes Res Clin Pract. 2009;83:176–182.

    Article  PubMed  CAS  Google Scholar 

  186. Heumuller S, Wind S, Barbosa-Sicard E, Schmidt HH, Busse R, Schroder K, Brandes RP. Apocynin is not an inhibitor of vascular NADPH oxidases but an antioxidant. Hypertension. 2008;51:211–217.

    Article  PubMed  CAS  Google Scholar 

  187. Baumer AT, Ten Freyhaus H, Sauer H, Wartenberg M, Kappert K, Schnabel P, Konkol C, Hescheler J, Vantler M, Rosenkranz S. Phosphatidylinositol 3-kinase-dependent membrane recruitment of Rac-1 and p47phox is critical for alpha-platelet-derived growth factor receptor-induced production of reactive oxygen species. J Biol Chem. 2008;283:7864–7876.

    Article  PubMed  CAS  Google Scholar 

  188. Diatchuk V, Lotan O, Koshkin V, Wikstroem P, Pick E. Inhibition of NADPH oxidase activation by 4-(2-aminoethyl)-benzenesulfonyl fluoride and related compounds. J Biol Chem. 1997;272:13292–13301.

    Article  PubMed  CAS  Google Scholar 

  189. ten Freyhaus H, Huntgeburth M, Wingler K, Schnitker J, Baumer AT, Vantler M, Bekhite MM, Wartenberg M, Sauer H, Rosenkranz S. Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. Cardiovasc Res. 2006;71:331–341.

    Article  PubMed  CAS  Google Scholar 

  190. Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ Res. 2001;89:408–414.

    Article  PubMed  CAS  Google Scholar 

  191. Zhou MS, Hernandez Schulman I, Pagano PJ, Jaimes EA, Raij L. Reduced NAD(P)H ­oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood ­pressure. Hypertension. 2006;47:81–86.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

T.J.A. and K.J-D. are supported by an Australian National Health and Medical Research Council (NH&MRC) Senior Research Fellowship. All three authors acknowledge support from the Australian NH&MRC and the Australian National Heart Foundation.

Author information

Authors and Affiliations

  1. Diabetic Complications Laboratory, JDRF Diabetes Division, Baker IDI Heart and Diabetes Institute, St Kilda Road Central, Melbourne, VIC, 8008, Australia

    Terri J. Allen

Authors
  1. Judy B. de Haan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karin A. Jandeleit-Dahm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Terri J. Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terri J. Allen .

Editor information

Editors and Affiliations

  1. Dept. Health & Caring Sciences, University Uppsala, Döbelnsgatan 2, Uppsala, 752 37, Sweden

    Samar Basu

  2. Dept. Surgical Sciences, Anaesthesiology, & Intensive Care, Uppsala University Hospital, Akademiska Sjukhuset, Uppsala, 751 85, Sweden

    Lars Wiklund

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

de Haan, J.B., Jandeleit-Dahm, K.A., Allen, T.J. (2011). Role of Oxidative Stress and Targeted Antioxidant Therapies in Experimental Models of Diabetic Complications. In: Basu, S., Wiklund, L. (eds) Studies on Experimental Models. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-956-7_1

Download citation

Publish with us

Policies and ethics

Search

Navigation