Skip to main content
Log in

The role of oxidative stress in diabetic complications

  • Review Article
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

The morbidity and mortality associated with diabetes is the result of the myriad complications related to the disease. One of the most explored hypotheses to explain the onset of complications is a hyperglycemia-induced increase in oxidative stress. Reactive oxygen species (ROS) are produced by oxidative phosphorylation, nicotinamide adenine dinucleotide phosphate oxidase (NADPH), xanthine oxidase, the uncoupling of lipoxygenases, cytochrome P450 monooxygenases, and glucose autoxidation. Once formed, ROS deplete antioxidant defenses, rendering the affected cells and tissues more susceptible to oxidative damage. Lipid, DNA, and protein are the cellular targets for oxidation, leading to changes in cellular structure and function. Recent evidence suggests ROS are also important as second messengers in the regulation of intracellular signaling pathways and, ultimately, gene expression. This review explores the production of ROS and the propagation and consequences of oxidative stress in diabetes.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. National Diabetes Information Clearinghouse. National Diabetes Statistics. Available from: http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm. Accessed September 8, 2004.

  2. Brownlee, M. and Cerami, A. (1981) The biochemistry of the complications of diabetes mellitus. Annu. Rev. Biochem. 50, 385–432.

    PubMed  CAS  Google Scholar 

  3. Kuusisto, J., Mykkanen, L., Pyorala, K., and Laakso, M. (1994) NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 43, 960–967.

    PubMed  CAS  Google Scholar 

  4. Luscher, T. F., Creager, M. A., Beckman, J. A., and Cosentino, F. (2003) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. Circulation 108, 1655–1661.

    PubMed  Google Scholar 

  5. Resnick, H. E. and Howard, B. V. (2002) Diabetes and cardiovascular disease. Annu. Rev. Med. 53, 245–267.

    PubMed  CAS  Google Scholar 

  6. Giugliano, D., Ceriello, A., and Paolisso, G. (1996) Oxidative stress and diabetic vascular complications. Diabetes Care 19, 257–267.

    PubMed  CAS  Google Scholar 

  7. Creager, M. A., Luscher, T. F., Cosentino, F., and Beckman, J. A. (2003) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation 108, 1527–1532.

    PubMed  Google Scholar 

  8. Brownlee, M. (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820.

    PubMed  CAS  Google Scholar 

  9. Rosen, P., Du, X., and Tschope, D. (1998) Role of oxygen derived radicals for vascular dysfunction in the diabetic heart: prevention by alphatocopherol? Mol. Cell. Biochem. 188, 103–111.

    PubMed  CAS  Google Scholar 

  10. Sheetz, M. J. and King, G. L. (2002) Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA. 288, 2579–2588.

    PubMed  CAS  Google Scholar 

  11. Roberts, L. J. and Morrow, J. D. (2000) Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo. Free Radic. Biol. Med. 28, 505–513.

    PubMed  CAS  Google Scholar 

  12. Pratico, D. (1999) F(2)-isoprostanes: sensitive and specific non-invasive indices of lipid peroxidation in vivo. Atherosclerosis 147, 1–10.

    PubMed  CAS  Google Scholar 

  13. Hyun, D. H., Lee, M., Hattori, N., Kubo, S., Mizuno, Y., Halliwell, B., et al. (2002) Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome. J. Biol. Chem. 277, 28572–28577.

    PubMed  CAS  Google Scholar 

  14. Pratico, D., Basili, S., Vieri, M., Cordova, C., Violi, F., and Fitzgerald, G. A. (1998) Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am. J. Respir. Crit. Care Med. 158 1709–1714.

    PubMed  CAS  Google Scholar 

  15. Kwong, L. K. and Sohal, R. S. (1998) Substrate and site specificity of hydrogen peroxide generation in mouse mitochondria. Arch. Biochem. Biophys. 350, 118–126.

    PubMed  CAS  Google Scholar 

  16. Yamagishi, S. I., Edelstein, D., Du, X. L., and Brownlee, M. (2001) Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. Diabetes 50, 1491–1494.

    PubMed  CAS  Google Scholar 

  17. Nishikawa, T., Edelstein, D., Du, X. L., Yamagishi, S., Matsumura, T., Kaneda, Y., et al. (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790.

    PubMed  CAS  Google Scholar 

  18. Du, Y., Miller, C. M., and Kern, T. S. (2003) Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic. Biol. Med. 35, 1491–1499.

    PubMed  CAS  Google Scholar 

  19. Du, X. L., Edelstein, D., Rossetti, L., Fantus, I. G., Goldberg, H., Ziyadeh, F., et al. (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc. Natl. Acad. Sci. USA 97, 12222–12226.

    PubMed  CAS  Google Scholar 

  20. Nedergaard, J. and Cannon, B. (2003) The ‘novel’ ‘uncoupling’ proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. Exp. Physiol. 88, 65–84.

    PubMed  CAS  Google Scholar 

  21. Korshunov, S. S., Skulachev, V. P., and Starkov, A. A. (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 416, 15–18.

    PubMed  CAS  Google Scholar 

  22. Echtay, K. S., Roussel, D., St-Pierre, J., Jekabsons, M. B., Cadenas, S., Stuart, J. A., et al. (2002) Superoxide activates mitochondrial uncoupling proteins. Nature, 415, 96–99.

    PubMed  CAS  Google Scholar 

  23. Murphy, M. P., Echtay, K. S., Blaikie, F. H., Asin-Cayuela, J., Cocheme, H. M., Green, K., et al. (2003) Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: studies using a mitochondria-targeted spin trap derived from alpha-phenyl-N-tert-butylnitrone. J. Biol. Chem. 278, 48534–48545.

    PubMed  CAS  Google Scholar 

  24. Pecqueur, C., Alves-Guerra, M. C., Gelly, C., Levi-Meyrueis, C., Couplan, E., Collins, S., et al. (2001) Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J. Biol. Chem. 276, 8705–8512.

    PubMed  CAS  Google Scholar 

  25. Zhou, Y. T., Shimabukuro, M., Koyama, K., Lee, Y., Wang, M. Y., Trieu, F., et al. (1997) Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proc. Natl. Acad. Sci. U. S. A. 94, 6386–6390.

    PubMed  CAS  Google Scholar 

  26. Bindokas, V. P., Kuznetsov, A., Sreenan, S., Polonsky, K. S., Roe, M. W., and Philipson, L. H. (2003) Visualizing superoxide production in normal and diabetic rat islets of Langerhans. J. Biol. Chem. 278, 9796–9801.

    PubMed  CAS  Google Scholar 

  27. Vincent, A. M., Olzmann, J. A., Brownlee, M., Sivitz, W. I., and Russell, J. W. (2004) Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death. Diabetes 53, 726–734.

    PubMed  CAS  Google Scholar 

  28. Krook, A., Digby, J., O'rahilly, S., Zierath, J. R., and Wallberg-Henriksson, H. (1998) Uncoupling protein 3 is reduced in skeletal muscle of NIDDM patients. Diabetes 47, 1528–1531.

    PubMed  CAS  Google Scholar 

  29. Blanc, J., Alves-Guerra, M. C., Espositio, B., Rousset, S., Gourdy, P., Ricquier, D., et al. (2003) Protective role of uncoupling protein 2 in atherosclerosis. Circulation 107, 388–390.

    PubMed  CAS  Google Scholar 

  30. Berman, R. S. and Martin, W. (1993) Arterial endothelial barrier dysfunction: actions of homocysteine and the hypoxanthine-xanthine oxidase free radical generating system. Br. J. Pharmacol. 108, 920–926.

    PubMed  CAS  Google Scholar 

  31. Mallat, Z., Nakamura, T., Ohan, J., Leseche, G. Tedgui, A., Maclouf, J., et al. (1999) The relationship of hydroxyeicosatetraenoic acids and F2-isoprostanes to plaque instability in human carotid atherosclerosis. J. Clin. Invest. 103, 421–427.

    PubMed  CAS  Google Scholar 

  32. Mattiasson, G., Shamloo, M., Gido, G., Mathi, K., Tomasevic, G., Yi, S., et al. (2003) Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat. Med. 9, 1062–1068.

    PubMed  CAS  Google Scholar 

  33. Teshima, Y., Akao, M., Jones, S. P., and Marban, E. (2003) Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ. Res. 93, 192–200.

    PubMed  CAS  Google Scholar 

  34. Henderson, L. M. and Chappel, J. B. (1996) NADPH oxidase of neutrophils. Biochim. Biophys. Acta 1273, 87–107.

    PubMed  Google Scholar 

  35. Lassegue, B. and Clempus, R. E. (2003) Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R277-R297.

    PubMed  CAS  Google Scholar 

  36. Inoguchi, T., Li, P., Umeda, F., Yu, H. Y., Kakimoto, M., Imamura, M., Aoki, T., Etoh, T., Hashimoto, T., Naruse, M., Sano, H., Utsumi, H., and Nawata, H. (2000) High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49, 1939–1945.

    PubMed  CAS  Google Scholar 

  37. Quagliaro, L., Piconi, L., Assaloni, R., Martinelli, L., Motz, E., and Ceriello, A. (2003) Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes 52, 2795–2804.

    PubMed  CAS  Google Scholar 

  38. Cosentino, F., Eto, M., De Paolis, P., Van Der Loo, B., Bachschmid, M., Ullrich, V., et al. (2003) High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation, 107, 1017–1023.

    PubMed  CAS  Google Scholar 

  39. Perner, A., Andresen, L., Pedersen, G., and Rask-Madsen, J. (2003) Superoxide production and expression of NAD(P)H oxidases by transformed and primary human colonic epithelial cells, Gut 52, 231–236.

    PubMed  CAS  Google Scholar 

  40. 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, 2603–2614.

    PubMed  CAS  Google Scholar 

  41. Hua, H., Munk, S., Goldberg, H., Fantus, I. G., and Whiteside, C. I. (2003) High glucose-suppressed endothelin-1 Ca2+ signaling via NADPH oxidase and diacylglycerol-sensitive protein kinase C isozymes in mesangial cells. J. Biol. Chem. 278, 33951–33962.

    PubMed  CAS  Google Scholar 

  42. Seno, T., Inoue, N., Gao, D., Okuda, M., Sumi, Y., Matsui, K., et al. (2001) Involvement of NADH/NADPH oxidase in human platelet ROS production. Thromb. Res. 103, 399–409.

    PubMed  CAS  Google Scholar 

  43. Dupuy, C., Virion, A., Ohayon, R., Kaniewski, J., Deme, D., and Pommier, J. (1991) Mechanism of hydrogen peroxide formation catalyzed by NADPH oxidase in thyroid plasma membrane. J. Biol. Chem. 266, 3739–3743.

    PubMed  CAS  Google Scholar 

  44. Mohanty, P., Hamouda, W., Garg, R., Aljada, A., Ghanim, H., and Dandona, P. (2000) Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J. Clin. Endocrinol. Metab. 85, 2970–2973.

    PubMed  CAS  Google Scholar 

  45. Babior, B. M. (1999) NADPH oxidase: an update. Blood 93, 1464–1476.

    PubMed  CAS  Google Scholar 

  46. Griendling, K. K., Sorescu, D., Lassegue, B., and Ushio-Fukai, M. (2000) Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler. Thromb. Vasc. Biol. 20, 2175–2183.

    PubMed  CAS  Google Scholar 

  47. Inoguchi, T., Sonta, T., Tsubouchi, H., Etoh, T., Kakimoto, M., Sonoda, N., et al. (2003) Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase. J. Am. Soc. Nephrol. 14, S227-S232.

    PubMed  CAS  Google Scholar 

  48. Li, J. M. and Shah, A. M. (2003) ROS generation by nonphagocytic NADPH oxidase: potential relevance in diabetic nephropathy. J. Am. Soc. Nephrol. 14, S221-S226.

    PubMed  CAS  Google Scholar 

  49. Lee, H. S., Son, S. M., Kim, Y. K., Hong, K. W., and Kim, C. D. (2003) NAD(P)H oxidase participates in the signaling events in high glucose-induced proliferation of vascular smooth muscle cells. Life Sci. 72, 2719–2730.

    PubMed  CAS  Google Scholar 

  50. Obrosova, I. G., Minchenko, A. G., Vasupuram, R., White, L., Abatan, O. I., Kumagai, A. K., et al. (2003) Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats. Diabetes 52, 864–871.

    PubMed  CAS  Google Scholar 

  51. Llorente, L., De La Fuente, H., Richaud-Patin, Y., Alvarado-De La Barrera, C., Diaz-Borjon, A., Lopez-Ponce, A., et al. (2000) Innate immune response mechanisms in non-insulin dependent diabetes mellitus patients assessed by flow cytoenzymology. Immunol. Lett. 74, 239–244.

    PubMed  Google Scholar 

  52. Christ, M., Bauersachs, J., Liebetrau, C., Heck, M., Gunther, A., and Wehling, M. (2002) Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes 51, 2648–2652.

    PubMed  CAS  Google Scholar 

  53. Fukui, T., Ishizaka, N., Rajagopalan, S., Laursen, J. B., Capers, Q. T., Taylor, W. R., et al. (1997) p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ. Res. 80, 45–51.

    PubMed  CAS  Google Scholar 

  54. Landmesser, U., Cai, H., Dikalov, S., Mccann, L., Hwang, J., Jo, H., et al. (2002) Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40, 511–515.

    PubMed  CAS  Google Scholar 

  55. Frustaci, A., Kajstura, J., Chimenti, C., Jakoniuk, I., Leri, A., Maseri, A., et al. (2000) Myocardial cell death in human diabetes. Circ. Res. 87, 1123–1132.

    PubMed  CAS  Google Scholar 

  56. Ye, G., Metreveli, N. S., Ren, J., and Epstein, P. N. (2003) Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 52, 777–783.

    PubMed  CAS  Google Scholar 

  57. Privratsky, J. R., Wold, L.E., Sowers, J. R., Quinn, M. T., and Ren, J. (2003) AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase. Hypertension 42, 206–212.

    PubMed  CAS  Google Scholar 

  58. Onozato, M. L., Tojo, A., Goto, A., Fujita, T., and Wilcox, C. S. (2002) Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int. 61, 186–194.

    PubMed  CAS  Google Scholar 

  59. Kajstura, J., Fiordaliso, F., Andreoli, A. M., Li, B., Chimenti, S., Medow, M. S., et al. (2001) IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 50, 1414–1424.

    PubMed  CAS  Google Scholar 

  60. Hink, U., Li, H., Mollnau, H., Oelze, M., Matheis, E., Hartmann, M., et al. (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ. Res. 88, E14-E22.

    PubMed  CAS  Google Scholar 

  61. Jain, S. K. (1989) Hyperglycemia can cause membrane lipid peroxidation and osmotic fragility in human red blood cells. J. Biol. Chem. 264, 21340–21345.

    PubMed  CAS  Google Scholar 

  62. Robertson, R. P., Harmon, J., Tran, P. O., Tanaka, Y., and Takahashi, H. (2003) Glucose toxicity in beta-cells: type 2 diabetes, good radcals gone bad, and the glutathione connection. Diabetes 52, 581–587.

    PubMed  CAS  Google Scholar 

  63. Wolff, S. P., Jiang, Z. Y., and Hunt, J. V. (1991) Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic. Biol. Med. 10, 339–352.

    PubMed  CAS  Google Scholar 

  64. Hunt, J. V., Dean, R. T., and Wolff, S. P. (1988) Hydroxyl radical production and autoxidative glycosylation. Glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes mellitus and ageing. Biochem. J. 256, 205–212.

    PubMed  CAS  Google Scholar 

  65. Hunt, J. V. and Wolff, S. P. (1991) Oxidative glycation and free radical production: a causal mechanism of diabetic complications. Free Radic. Res. Commun. 12–13, 115–123.

    PubMed  Google Scholar 

  66. Chace, K. V., Carubelli, R., and Nordquist, R. E. (1991) The role of nonenzymatic glycosylation, transition metals, and free radicals in the formation of collagen aggregates. Arch. Biochem. Biophys. 288, 473–480.

    PubMed  CAS  Google Scholar 

  67. Hicks, M., Delbridge, L., Yue, D. K., and Reeve, T. S. (1988) Catalysis of lipid peroxidation by glucose and glycosylated collagen. Biochem. Biophys. Res. Commun. 151, 649–655.

    PubMed  CAS  Google Scholar 

  68. Ou, P. and Wolff, S. P. (1994) Erythrocyte catalase inactivation (H2O2 production) by ascorbic acid and glucose in the presence of aminotriazole: role of transition metals and relevance to diabetes. Biochem. J. 303, 935–939.

    PubMed  CAS  Google Scholar 

  69. Lomonosova, E. E., Kirsch, M., and De Groot, H. (1998) Calcium vs. iron-mediated processes in hydrogen peroxide toxicity to L929 cells: effects of glucose. Free Radic. Biol. Med. 25, 493–503.

    PubMed  CAS  Google Scholar 

  70. Graier, W. F., Simecek, S., Kukovetz, W. R., and Kostner, G. M. (1996) High D-glucose-induced changes in endothelial Ca2+/EDRF signaling are due to generation of superoxide anions. Diabetes 45, 1386–1395.

    PubMed  CAS  Google Scholar 

  71. Wolff, S. P. and Dean, R. T. (1987) Glucose autoxidation and protein modification. The potential role of ‘autoxidative glycosylation’ in diabetes. Biochem. J. 245, 243–250.

    PubMed  CAS  Google Scholar 

  72. Massion, P. B., Feron, O., Dessy, C., and Balligand, J. L. (2003) Nitric oxide and cardiac function: ten years after, and continuing. Circ. Res. 93, 388–398.

    PubMed  CAS  Google Scholar 

  73. Zou, M. H., Shi, C., and Cohen, R. A. (2002) Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J. Clin. Invest. 109, 817–826.

    PubMed  CAS  Google Scholar 

  74. Rosen, G. M., Tsai, P., and Pou, S. (2002) Mechanism of free-radical generation by nitric oxide synthase. Chem. Rev. 102, 1191–1200.

    PubMed  CAS  Google Scholar 

  75. Harrison, D. G. (1997) Cellular and molecular mechanisms of endothelial cell dysfunction. J. Clin. Invest. 100, 2153–2157.

    PubMed  CAS  Google Scholar 

  76. Wever, R. M., Luscher, T. F., Cosentino, F., and Rabelink, T. J. (1998) Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 97, 108–112.

    PubMed  CAS  Google Scholar 

  77. Ceriello, A. (2003) New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 26, 1589–1596.

    PubMed  CAS  Google Scholar 

  78. Shinozaki, K., Kashiwagi, A., Nishio, Y., Okamura, T., Yoshida, Y., Masada, M., et al. (1999) Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2-imbalance in insulin-resistant rat aorta. Diabetes 48, 2437–2445.

    PubMed  CAS  Google Scholar 

  79. Cosentino, F., Hishikawa, K., Katusic, Z. S., and Luscher, T. F. (1997) High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 96, 25–28.

    PubMed  CAS  Google Scholar 

  80. El-Remessy, A. B., Behzadian, M. A., Abou-Mohamed G., Franklin, T., Caldwell, R. W., and Caldwell, R. B. (2003) Experimental diabetes causes breakdown of the blood-retina barrier by a mechanism involving tyrosine nitration and increases in expression of vascular endothelial growth factor and urokinase plasminogen activator receptor. Am. J. Pathol. 162, 1995–2004.

    PubMed  CAS  Google Scholar 

  81. Kowluru, R. A. (2003) Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 52, 818–823.

    PubMed  CAS  Google Scholar 

  82. Shinozaki, K., Nishio, Y., Okamura, T., Yoshida, Y., Maegawa, H., Kojima, H., et al. (2000) Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ. Res. 87, 566–573.

    PubMed  CAS  Google Scholar 

  83. Reif, A., Frohlich, L. G., Kotsonis, P., Frey, A., Bommel, H. M., Wink, D. A., et al. (1999) Tetrahydrobiopterin inhibits monomerization and is consumed during catalysis in neuronal NO synthase. J. Biol. Chem. 274, 24921–24929.

    PubMed  CAS  Google Scholar 

  84. Kwon, N. S., Nathan, C. F., and Stuehr, D. J. (1989) Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J. Biol. Chem. 264, 20496–20501.

    PubMed  CAS  Google Scholar 

  85. Heitzer, T., Krohn, K., Albers, S., and Meinertz, T. (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia 43, 1435–1438.

    PubMed  CAS  Google Scholar 

  86. Szabo, C., Mabley, J. G., Moeller, S. M., Shimanovich, R., Pacher, P., Virag, L., et al. (2002) Part I: pathogenetic role of peroxynitrite in the development of diabetes and diabetic vascular complications: studies with FP15, a novel potent peroxynitrite decomposition catalyst. Mol. Med. 8, 571–580.

    PubMed  CAS  Google Scholar 

  87. Turko, I. V., Li, L., Aulak, K. S., Stuehr, D. J., Chang, J. Y., and Murad, F. (2003) Protein tyrosine nitration in the mitochondria from diabetic mouse heart. Implications to dysfunctional mitochondria in diabetes. J. Biol. Chem. 278, 33972–33977.

    PubMed  CAS  Google Scholar 

  88. Hoeldtke, R. D., Bryner, K. D., Mcneill, D. R. Hobbs, G. R., and Baylis, C. (2003) Peroxynitrite versus nitric oxide in early diabetes. Am. J. Hypertens. 16, 761–766.

    PubMed  CAS  Google Scholar 

  89. Hoeldtke, R. D., Bryner, K. D., Mcneill, D. R., Hobbs, G. R., Riggs, J. E., Warehime, S. S., et al. (2002) Nitrosative stress, uric acid, and peripheral nerve function in early type 1 diabetes. Diabetes 51, 2817–2825.

    PubMed  CAS  Google Scholar 

  90. Kossenjans, W., Eis, A., Sahay, R., Brockman, D., and Myatt, L. (2000) Role of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia. Am. J. Physiol. Heart Circ. Physiol. 278, H1311-H1319.

    PubMed  CAS  Google Scholar 

  91. Pritsos, C. A. (2000) Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. Chem. Biol. Interact. 129, 195–208.

    PubMed  CAS  Google Scholar 

  92. Harrison, R. (2002) Structure and function of xanthine oxidoreductase: where are we now? Free Radic. Biol. Med. 33, 774–797.

    PubMed  CAS  Google Scholar 

  93. Garattini, E., Mendel, R., Romao, M. J., Wright, R., and Terao, M. (2003) Mammalian molybdo-flavoenzymes, an expending family of proteins: structure, genetics, regulation, function and pathophysiology. Biochem. J. 372, 15–32.

    PubMed  CAS  Google Scholar 

  94. Paler-Martinez, A., Panus, P. C., Chumley, P. H., Ryan, U., Hardy, M. M., and Freeman, B. A. (1994) Endogenous xanthine oxidase does not significantly contribute to vascular endothelial production of reactive oxygen species. Arch. Biochem. Biophys. 311, 79–85.

    PubMed  CAS  Google Scholar 

  95. Friedl, H. P., Smith, D. J., Till, G. O., Thomson, P. D., Louis, D. S., and Ward, P. A. (1990) Ischemia-reperfusion in humans. Appearance of xanthine oxidase activity. Am. J. Pathol. 136, 491–495.

    PubMed  CAS  Google Scholar 

  96. Salas, A., Panes, J., Elizalde, J. I., Granger, D. N., and Pique, J. M. (1999) Reperfusion-induced oxidative stress in diabetes: cellular and enzymatic sources. J. Leukoc. Biol. 66, 59–66.

    PubMed  CAS  Google Scholar 

  97. Desco, M. C., Asensi, M., Marquez, R., Martinez-Valls, J., Vento, M., Pallardo, F. V., et al. (2002) Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes 51, 1118–1124.

    PubMed  CAS  Google Scholar 

  98. Butler, R., Morris, A. D., Belch, J. J., Hill, A., and Struthers, A. D. (2000) Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35, 746–751.

    PubMed  CAS  Google Scholar 

  99. White, C. R., Darley-Usmar, V., Berrington, W. R., Mcadams, M., Gore, J. Z., Thompson, J. A., et al. (1996) Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits. Proc. Natl. Acad. Sci. U.S.A. 93, 8745–8749.

    PubMed  CAS  Google Scholar 

  100. Aliciguzel, Y., Ozen, I., Aslan, M., and Karayalcin, U. (2003) Activities of xanthine oxidoreductase and antioxidant enzymes in different tissues of diabetic rats. J. Lab. Clin. Med. 142, 172–177.

    PubMed  CAS  Google Scholar 

  101. Coon, M. J. (2003) Multiple oxidants and multiple mechanisms in cytochrome P450 catalysis. Biochem. Biophys. Res. Commun. 312, 163–168.

    PubMed  CAS  Google Scholar 

  102. Guengerich, F. P. (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. Arch. Biochem. Biophys. 409, 59–71.

    PubMed  Google Scholar 

  103. Caro, A. A. and Cederbaum, A. I. (2004) Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu. Rev. Pharmacol. Toxicol. 44, 27–42.

    PubMed  CAS  Google Scholar 

  104. Loida, P. J. and Sligar, S. G. (1993) Molecular recognition in cytochrome P-450: mechanism for the control of uncoupling reactions. Biochemistry 32, 11530–11538.

    PubMed  CAS  Google Scholar 

  105. Leclercq, I. A., Farrell, G. C., Field, J., Bell, D. R., Gonzalez, F. J., and Robertson, G. R. (2000) CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J. Clin. Invest. 105, 1067–1075.

    PubMed  CAS  Google Scholar 

  106. Wang, Z., Hall, S. D., Maya, J. F., Li, L., Asghar, A., and Gorski, J. C. (2003) Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. Br. J. Clin. Pharmacol. 55, 77–85.

    PubMed  CAS  Google Scholar 

  107. Hannon-Fletcher, M. P., O'kane, M. J., Moles, K. W., Barnett, Y. A., and Barnett, C. R. (2001) Lymphocyte cytochrome P450-CYP2E1 expression in human IDDM subjects. Food Chem. Toxicol. 39, 125–132.

    PubMed  CAS  Google Scholar 

  108. Haufroid V., Ligocka, D., Buysschaert, M., Horsmans, Y., and Lison, D. (2003) Cytochrome P4502E1 (CYP2E1) expression in peripheral blood lymphocytes: evaluation in hepatitis C and diabetes. Eur. J. Clin. Pharmacol. 59, 29–33.

    PubMed  CAS  Google Scholar 

  109. Leclercq, I. A., Field, J., Enriquez, A., Farrell, G. C., and Robertson, G. R. (2000) Constitutive and inducible expression of hepatic CYP2E1 in leptin-deficient ob/ob mice. Biochem. Biophys. Res. Commun. 268, 337–344.

    PubMed  CAS  Google Scholar 

  110. Favreau, L. V., Malchoff, D. M., Mole, J. E., and Schenkman, J. B. (1987) Responses to insulin by two forms of rat hepatic microsomal cytochrome P-450 that undergo major (RLM6) and minor (RLM5b) elevations in diabetes. J. Biol. Chem. 262, 14319–14326.

    PubMed  CAS  Google Scholar 

  111. Takatori, A., Akahori, M., Kawamura, S., Itagaki, S., and Yoshikawa, Y. (2002) The effects of diabetes with hyperlipidemia on P450 expression in APA hamster livers. J.Biochem. Mol. Toxicol. 16, 174–181.

    PubMed  CAS  Google Scholar 

  112. Enriquez, A., Leclercq, I., Farrell, G. C., and Robertson, G. (1999) Altered expression of hepatic CYP2E1 and CYP4A in obese diabetic ob/ob mice, and fa/fa Zucker rats. Biochem. Biophys. Res. Commun. 255, 300–306.

    PubMed  CAS  Google Scholar 

  113. Zangar, R. C. and Novak, R. F. (1997) Effects of fatty acids and ketone bodies on cytochromes P450 2B, 4A, and 2E1 expression in primary cultured rat hepatocytes. Arch. Biochem. Biophys. 337, 217–224.

    PubMed  CAS  Google Scholar 

  114. Iber, H., Li-Masters, T., Chen, Q., Yu, S., and Morgan, E. T. (2001) Regulation of hepatic cytochrome P450 2C11 via cAMP: implications for down-regulation in diabetes, fasting, and inflammation. J. Pharmacol. Exp. Ther. 297, 174–180.

    PubMed  CAS  Google Scholar 

  115. Pass, G. J., Becker, W., Kluge, R., Linnartz, K., Plum, L., Giesen, K., et al. (2002) Effect of hyper-insulinemia and type 2 diabetes-like hyperglycemia on expression of hepatic cytochrome p450 and glutathione S-transferase isoforms in a New Zealand obese-derived mouse backcross population. J. Pharmacol. Exp. Ther. 302, 442–450.

    PubMed  CAS  Google Scholar 

  116. Chanez, P., Bonnans, C., Chavis, C., and Vachier, I. (2002) 15-lipoxygenase: a Janus enzyme?. Am. J. Respir. Cell. Mol. Biol. 27, 655–658.

    PubMed  CAS  Google Scholar 

  117. Brash, A. R. (1999) Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J. Biol. Chem. 274, 23679–23682.

    PubMed  CAS  Google Scholar 

  118. Furstenberger, G., Marks, F., and Krieg, P. (2002) Arachidonate 8(S)-lipoxygenase. Prostaglandins Other Lipid Mediat. 68–69, 235–243.

    PubMed  Google Scholar 

  119. Yoshimoto, T. and Takahashi, Y. (2002) Arachidonate 12-lipoxygenases. Prostaglandins Other Lipid Mediat. 68–69, 245–262.

    PubMed  Google Scholar 

  120. Kuhn, H., Walther, M., and Kuban, R. J. (2002) Mammalian arachidonate 15-lipoxygenases structure, function, and biological implications. Prostaglandins Other Lipid Mediat. 68–69, 263–290.

    PubMed  Google Scholar 

  121. Schewe, T. (2002) 15-lipoxygenase-1: a prooxidant enzyme. Biol. Chem. 383, 365–374.

    PubMed  CAS  Google Scholar 

  122. Conrad, D. J. (1999) The arachidonate 12/15 lipoxygenases. A review of tissue expression and biologic function. Clin. Rev. Allergy Immunol. 17, 71–89.

    PubMed  CAS  Google Scholar 

  123. Funk, C. D. and Cyrus, T. (2001) 12/15-lipoxygenase, oxidative modification of LDL and atherogenesis. Trends Cardiovasc. Med. 11, 116–124.

    PubMed  CAS  Google Scholar 

  124. Natarajan, R. and Nadler, J. L. (2003) Lipoxygenases and lipid signaling in vascular cells in diabetes. Front Biosci. 8, s783-s795.

    PubMed  CAS  Google Scholar 

  125. Dandona, P. and Aljada, A. (2002) A rational approach to pathogenesis and treatment of type 2 diabetes mellitus, insulin resistance, inflammation, and atherosclerosis. Am. J. Cardiol. 90, 27G-33G.

    PubMed  CAS  Google Scholar 

  126. Hatley, M. E., Srinivasan, S., Reilly, K. B., Bolick, D. T., and Hedrick, C. C. (2003) Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice. J. Biol. Chem. 278, 25369–25375.

    PubMed  CAS  Google Scholar 

  127. Patricia, M. K., Natarajan, R., Dooley, A. N., Hernandez, F., Gu, J. L., Berliner, J. A., et al. (2001) Adenoviral delivery of a leukocyte-type 12 lipoxygenase ribozyme inhibits effects of glucose and platelet-derived growth factor in vascular endothelial and smooth muscle cells. Circ. Res. 88, 659–665.

    PubMed  CAS  Google Scholar 

  128. Bleich, D., Chen, S., Zipser, B., Sun, D., Funk, C. D., and Nadler, J. L. (1999) Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice. J. Clin. Invest. 103, 1431–1436.

    PubMed  CAS  Google Scholar 

  129. Maritim, A. C., Sanders, R. A., and Watkins, J. B., 3rd (2003) Diabetes, oxidative stress, and antioxidants: a review. J. Biochem. Mol. Toxicol. 17, 24–38.

    PubMed  CAS  Google Scholar 

  130. Sundaram, R. K., Bhaskar, A., Vijayalingam, S., Viswanathan, M., Mohan, R., and Shanmugasundaram, K. R. (1996) Antioxidant status and lipid peroxidation in type II diabetes mellitus with and without complications. Clin. Sci. (Lond.) 90, 255–260.

    CAS  Google Scholar 

  131. Nourooz-Zadeh, J., Rahimi, A., Tajaddini-Sarmadi, J., Tritschler, H., Rosen, P., Halliwell, B., et al. (1997) Relationships between plasma measures of oxidative stress and metabolic control in NIDDM. Diabetologia 40, 647–653.

    PubMed  CAS  Google Scholar 

  132. Martin-Gallan, P., Carrascosa, A., Gussinye, M., and Dominguez, C. (2003) Biomarkers of diabetes-associated oxidative stress and antioxidant status in young diabetic patients with or without subclinical complications. Free Radic. Biol. Med. 34, 1563–1574.

    PubMed  CAS  Google Scholar 

  133. Davison, G. W., George, L., Jackson, S. K., Young, I. S., Davies, B., Bailey, D. M., et al. (2002) Exercise, free radicals, and lipid peroxidation in type 1 diabetes mellitus. Free Radic. Biol. Med. 33, 1543–1551.

    PubMed  CAS  Google Scholar 

  134. Wilson, M. (1998) The Effect of Hyperglycemia on Erythrocyte Phospholipid Organization. Indiana University: Bloomington, IN.

    Google Scholar 

  135. Jain, S. K., Palmer, M., and Chen, Y. (1999) Effect of vitamin E and N-acetylcysteine on phosphatidylserine externalization and induction of coagulation by high-glucose-treated human erythrocytes. Metabolism 48, 957–959.

    PubMed  CAS  Google Scholar 

  136. Trachtman, H. (1994) Vitamin E prevents glucose-induced lipid peroxidation and increased collagen production in cultured rat mesangial cells. Microvasc. Res. 47, 232–239.

    PubMed  CAS  Google Scholar 

  137. Sharpe, P. C., Yue, K. K., Catherwood, M. A., Mcmaster, D., and Trimble, E. R. (1998) The effects of glucose-induced oxidative stress on growth and extracellular matrix gene expression of vascular smooth muscle cells. Diabetologia 41, 1210–1219.

    PubMed  CAS  Google Scholar 

  138. Jachec, W., Tomasik, A., Tarnawski, R., and Chwalinska, E. (2002) Evidence of oxidative stress in the renal cortex of diabetic rats: favourable effect of vitamin E. Scand. J. Clin. Lab. Invest. 62, 81–88.

    PubMed  CAS  Google Scholar 

  139. Jain, S. K., Mcvie, R., Jaramillo, J. J., Palmer, M., Smith, T., Meachum, Z. D., et al. (1996) The effect of modest vitamin E supplementation on lipid peroxidation products and other cardiovascular risk factors in diabetic patients. Lipids 31 Suppl, S87-S90.

    PubMed  CAS  Google Scholar 

  140. Jain, S. K., Krueger, K. S., Mcvie, R., Jaramillo, J. J., Palmer, M., and Smith, T. (1998) Relationship of blood thromboxane-B2 (TxB2) with lipid peroxides and effect of vitamin E and placebo supplementation on TxB2 and lipid peroxide levels in type 1 diabetic patients. Diabetes Care 21, 1511–1516.

    PubMed  CAS  Google Scholar 

  141. May, J. M., Qu, Z. C., and Morrow, J. D. (1996) Interaction of ascorbate and alpha-tocopherol in resealed human erythrocyte ghosts. Transmembrane electron transfer and protection from lipid peroxidation. J. Biol. Chem. 271, 10577–10582.

    PubMed  CAS  Google Scholar 

  142. Ford, E. S., Mokdad, A. H., Giles, W. H., and Brown, D. W. (2003) The metabolic syndrome and antioxidant concentrations: findings from the Third National Health and Nutrition Examination Survey. Diabetes 52, 2346–2352.

    PubMed  CAS  Google Scholar 

  143. Vanderjagt, D. J., Harrison, J. M., Ratliff, D. M., Hunsaker, L. A., and Vander Jagt, D. L. (2001) Oxidative stress indices in IDDM subjects with and without long-term diabetic complications. Clin. Biochem. 34, 265–270.

    PubMed  CAS  Google Scholar 

  144. Obrosova, I. G., Fathallah, L., Liu, E., and Nourooz-Zadeh, J. (2003) Early oxidative stress in the diabetic kidney: effect of DL-alpha-lipoic acid. Free Radic. Biol. Med. 34, 186–195.

    PubMed  CAS  Google Scholar 

  145. Kashiba, M., Oka, J., Ichikawa, R., Kasahara, E., Inayama, T., Kageyama, A., et al. (2002) Impaired ascorbic acid metabolism in streptozotocin-induced diabetic rats. Free Radic. Biol. Med. 33, 1221–1230.

    PubMed  CAS  Google Scholar 

  146. Catherwood, M. A., Powell, L. A., Anderson, P., Mcmaster, D., Sharpe, P. C., and Trimble, E. R. (2002) Glucose-induced oxidative stress in mesangial cells. Kidney Int. 61, 599–608.

    PubMed  CAS  Google Scholar 

  147. Hamilton, J. S., Powell, L. A., Mcmaster, C., Mcmaster, D., and Trimble, E. R. (2003) Interaction of glucose and long chain fatty acids (C18) on antioxidant defences and free radical damage in porcine vascular smooth muscle cells in vitro. Diabetologia 46, 106–114.

    PubMed  CAS  Google Scholar 

  148. Van Dam, P. S., Van Asbeck, B. S., Van Oirschot, J. F., Biessels, G. J., Hamers, F. P., and Marx, J. J. (2001) Glutathione and alpha-lipoate in diabetic rats: nerve function, blood flow and oxidative state. Eur. J. Clin. Invest. 31, 417–424.

    PubMed  Google Scholar 

  149. Yilmaz, O., Ozkan, Y., Yildirim, M., Ozturk, A. I., and Ersan, Y. (2002) Effects of alpha lipoic acid, ascorbic acid-6-palmitate, and fish oil on the glutathione, malonaldehyde, and fatty acids levels in erythrocytes of streptozotocin induced diabetic male rats. J. Cell. Biochem. 86, 530–539.

    PubMed  CAS  Google Scholar 

  150. Aragno, M., Parola, S., Brignardello, E., Manti, R., Betteto, S., Tamagino, E., et al. (2001) Oxidative stress and eicosanoids in the kidneys of hyperglycemic rats treated with dehydroepian drosterone. Free Rad. Biol. Med. 31, 935–942.

    PubMed  CAS  Google Scholar 

  151. Tagami, S., Kondo, T., Yoshida, K., Hirokawa, J., Ohtsuka, Y., and Kawakami, Y. (1992) Effect of insulin on impaired antioxidant activities in aortic endothelial cells from diabetic rabbits. Metabolism 41, 1053–1058.

    PubMed  CAS  Google Scholar 

  152. Sailaja, Y. R., Baskar, R., and Saralakumari, D. (2003) The antioxidant status during maturation of reticulocytes to erythrocytes in type 2 diabetics. Free Radic. Biol. Med. 35, 133–139.

    PubMed  CAS  Google Scholar 

  153. Murakami, K., Kondo, T., Ohtsuka, Y., Fujiwara, Y., Shimada, M., and Kawakami Y. (1989) Impairment of glutathione metabolism in erythrocytes from patients with diabetes mellitus. Metabolism 38, 753–758.

    PubMed  CAS  Google Scholar 

  154. Thomas, G., Skrinska, V., Lucas, F. V., and Schumacher, O. P. (1985) Platelet glutathione and thromboxane synthesis in diabetes. Diabetes 34, 951–954.

    PubMed  CAS  Google Scholar 

  155. Chari, S. N., Nath, N., and Rathi, A. B. (1984) Glutathione and its redox system in diabetic polymorphonuclear leukocytes. Am. J. Med. Sci. 287, 14–15.

    PubMed  CAS  Google Scholar 

  156. Liang, Q., Carlson, E. C., Donthi, R. V., Kralik, P. M., Shen, X., and Epstein, P. N. (2002) Overexpression of metallothionein reduces diabetic cardiomyopathy. Diabetes 51, 174–181.

    PubMed  CAS  Google Scholar 

  157. Thornalley, P. J., Mclellan, A. C., Lo, T. W., Benn, J., and Sonksen, P. H. (1996) Negative association between erythrocyte reduced glutathione concentration and diabetic complications. Clin. Sci. (Lond) 91, 575–582.

    CAS  Google Scholar 

  158. Packer, L., Kraemer, K., and Rimbach, G. (2001) Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17, 888–895.

    PubMed  CAS  Google Scholar 

  159. Coppey, L. J., Gellett, J. S., Davidson, E. P., Dunlap, J. A., Lund, D. D., and Yorek, M. A. (2001) Effect of antioxidant treatment of strep-tozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 50, 1927–1937.

    PubMed  CAS  Google Scholar 

  160. Obrosova, I. G., Fathallah, L., and Greene, D. A. (2000) Early changes in lipid peroxidation and antioxidative defense in diabetic rat retina: effect of DL-alpha-lipoic acid. Eur. J. Pharmacol. 398, 139–146.

    PubMed  CAS  Google Scholar 

  161. Bojunga, J., Dresar-Mayert, B., Usadel, K. H., Kusterer, K., and Zeuzem, S. (2004) Antioxidative treatment reverses imbalances of nitric oxide synthase isoform expression and attenuates tissue-cGMP activation in diabetic rats. Biochem. Biophys. Res. Commun. 316, 771–780.

    PubMed  CAS  Google Scholar 

  162. Stevens, M. J., Obrosova, J., Cao, X., Van Huysen, C., and Greene, D. A. (2000) Effects of DL-alpha-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy. Diabetes 49, 1006–1015.

    PubMed  CAS  Google Scholar 

  163. Heitzer, T., Finckh, B., Albers, S., Krohn, K., Kohlschutter, A., and Meinertz, T. (2001) Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Free Radic. Biol. Med. 31, 53–61.

    PubMed  CAS  Google Scholar 

  164. Ametov, A. S., Barinov, A., Dyck, P. J., Hermann, R., Kozlova, N., Litchy, W. J., et al. (2003) The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYD-NEY trial. Diabetes Care 26, 770–776.

    PubMed  CAS  Google Scholar 

  165. Midaoui, A. E., Elimadi, A., Wu, L., Haddad, P. S., and De Champlain, J. (2003) Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production. Am. J. Hypertens. 16, 173–179.

    PubMed  Google Scholar 

  166. Arthur, J. R. (2000) The glutathione peroxidases. Cell. Mol. Life. Sci. 57, 1825–1835.

    PubMed  CAS  Google Scholar 

  167. Hodgkinson, A. D., Bartlett, T., Oates, P. J., Millward, B. A., and Demaine, A. G. (2003) The response of antioxidant genes to hyperglycemia is abnormal in patients with type 1 diabetes and diabetic nephropathy. Diabetes 52, 846–851.

    PubMed  CAS  Google Scholar 

  168. Salvemini, F., Franze, A., Iervolino, A., Filosa, S., Salzano, S., and Ursini, M. V. (1999) Enhanced glutathione levels and oxidoresistance mediated by increased glucose-6-phosphate dehydrogenase expression. J. Biol. Chem. 274, 2750–2757.

    PubMed  CAS  Google Scholar 

  169. Pandolfi, P. P., Sonati, F., Rivi, R., Mason, P., Grosveld, F., and Luzzatto, L. (1995) Targeted disruption of the housekeeping gene encoding glucose-6-phosphate dehydrogenase: (G6PD): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress. EMBO J. 14, 5209–5215.

    PubMed  CAS  Google Scholar 

  170. Leopold, J. A., Cap, A., Scribner, A. W., Stanton, R. C., and Loscalzo, J. (2001) Glucose-6-phosphate dehydrogenase deficiency promotes endothelial oxidant stress and decreases endothelial nitric oxide bioavailability. FASEB J. 15, 1771–1773.

    PubMed  CAS  Google Scholar 

  171. Ingrosso, D., Cimmino, A., D'angelo, S., Alfinito, F., Zappia, V., and Galletti, P. (2002) Protein methylation as a marker of aspartate damage in glucose-6-phosphate dehydrogenase-deficient erythrocytes: role of oxidative stress. Eur. J. Biochem. 269, 2032–2039.

    PubMed  CAS  Google Scholar 

  172. Ho, H. Y., Cheng, M. L., Lu, F. J., Chou, Y. H., Stern, A., Liang, C. M., et al. (2000) Enhanced oxidative stress and accelerated cellular senescence in glucose-6-phosphate dehydrogenase (G6PD)-deficient human fibroblasts. Free Radic. Biol. Med. 29, 156–169.

    PubMed  CAS  Google Scholar 

  173. Zhang, Z., Apse, K., Pang, J., and Stanton, R. C. (2000) High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells. J. Biol. Chem. 275, 40042–40047.

    PubMed  CAS  Google Scholar 

  174. Donma, O., Yorulmaz, E., Pekel, H., and Suyugul, N. (2002) Blood and lens lipid peroxidation and antioxidant status in normal individuals, senile and diabetic cataractous patients. Curr. Eye Res. 25, 9–16.

    PubMed  Google Scholar 

  175. Otton, R., Mendonca, J. R., and Curi, R. (2002) Diabetes causes marked changes in lymphocyte metabolism. J. Endocrinol. 174, 55–61.

    PubMed  CAS  Google Scholar 

  176. Sochor, M., Kunjara S., Greenbaum, L., and Mclean, P. (1986) Renal hypertrophy in experimental diabetes: effect of diabetes on the pathways of glucose metabolism: differential response in adult and immature rats. Biochem. J. 234, 573–577.

    PubMed  CAS  Google Scholar 

  177. Asahina, T., Kashiwagi, A., Nishio, Y., Ikebuchi, M., Harada, N., Tanaka, Y., et al. (1995) Impaired activation of glucose oxidation and NADPH supply in human endothelial cells exposed to H2O2 in high-glucose medium. Diabetes 44, 520–526.

    PubMed  CAS  Google Scholar 

  178. Zelko, I. N., Mariani, T. J., and Folz, R. J. (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic. Biol. Med. 33, 337–349.

    PubMed  CAS  Google Scholar 

  179. Derubertis, F. R., Craven, P. A., Melhem, M. F., and Salah, E. M. (2004) Attenuation of renal injury in db/db mice overexpressing superoxide dismutase: evidence for reduced superoxide-nitric oxide interaction. Diabetes 53, 762–868.

    PubMed  CAS  Google Scholar 

  180. Karasu, C. (1999) Increased activity of H2O2 in aorta isolated from chronically streptozotocin-diabetic rats: effects of antioxidant enzymes and enzymes inhibitors. Free Radic. Biol. Med. 27, 16–27.

    PubMed  CAS  Google Scholar 

  181. Kirkman, H. N., Rolfo, M., Ferraris, A. M., and Gaetani, G. F. (1999) Mechanisms of protection of catalase by NADPH. J. Biol. Chem. 274, 13908–13914.

    PubMed  CAS  Google Scholar 

  182. Goth, L. and Eaton, J. W. (2000) Hereditary catalase deficiencies and increased risk of diabetes. Lancet 356, 1820–1821.

    PubMed  CAS  Google Scholar 

  183. Goth, L., Lenkey, A., and Bigler, W. N. (2001) Blood catalase deficiency and diabetes in Hungary. Diabetes Care 24, 1839–1840.

    PubMed  CAS  Google Scholar 

  184. Srivastava, S., Dixit, B. L., Cai, J., Sharma, S., Hurst, H. E., Bhatnagar, A et al. (2000) Metabolism of lipid peroxidation product, 4-hydroxynonenal (HNE) in rat erythrocytes: role of aldose reductase. Free Radic. Biol. Med. 29, 642–651.

    PubMed  CAS  Google Scholar 

  185. Chandra, D., Jackson, E. B., Ramana, K. V., Kelley, R., Srivastava, S. K., and Bhatnagar, A. (2002) Nitric oxide prevents aldose reductase activation and sorbitol accumulation during diabetes. Diabetes 51, 3095–3101.

    PubMed  CAS  Google Scholar 

  186. Lee, A. Y., Chung, S. K., and Chung, S. S. (1995) Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc. Natl. Acad. Sci. U. S. A. 92, 2780–2784.

    PubMed  CAS  Google Scholar 

  187. Nishimura, C., Hotta, Y., Gui, T., Seko, A., Fujimaki, T., Ishikawa, T., et al. (1997) The level of erythrocyte aldose reductase is associated with the severity of diabetic retinopathy. Diabetes Res. Clin. Pract. 37, 173–177.

    PubMed  CAS  Google Scholar 

  188. Malone, J. I., Knox, G., Benford, S., and Tedesco, T. A. (1980) Red cell sorbitol: an indicator of diabetic control. Diabetes 29, 861–864.

    PubMed  CAS  Google Scholar 

  189. Oishi, N., Kubo, E., Takamura, Y., Maekawa, K., Tanimoto, T., and Akagi, Y. (2002) Correlation between erythrocyte aldose reductase level and human diabetic retinopathy. Br. J. Ophthalmol. 86, 1363–1366.

    PubMed  CAS  Google Scholar 

  190. Nakamura, J., Koh, N., Sakakibara, F., Hamada, Y., Wakao, T., Hara, T., et al. (1995) Polyol pathway, 2,3-diphosphoglycerate in erythrocytes and diabetic neuropathy in rats. Eur. J. Pharmacol. 294, 207–214.

    PubMed  CAS  Google Scholar 

  191. Takahashi, Y., Tachikawa, T., Ito, T., Takayama, S., Omori, Y., and Iwamoto, Y. (1998) Erythrocyte aldose reductase protein: a clue to elucidate risk factors for diabetic neuropathies independent of glycemic control. Diabetes Res. Clin. Pract. 42, 101–107.

    PubMed  CAS  Google Scholar 

  192. Maeda, S., Haneda, M., Yasuda, H., Tachikawa, T., Isshiki, K., Koya, D., et al. (1999) Diabetic nephropathy is not associated with the dinucleotide repeat polymorphism upstream of the aldose reductase (ALR2) gene but with erythrocyte aldose reductase content in Japanese subjects with type 2 diabetes. Diabetes 48, 420–422.

    PubMed  CAS  Google Scholar 

  193. Raccah, D., Coste, T., Cameron, N. E., Dufayet, D., Vague, P., and Hohman, T. C. (1998) Effect of the aldose reductase inhibitor tolrestat on nerve conduction velocity, Na/K ATPase activity, and polyols in red blood cells, sciatic nerve, kidney cortex, and kidney medulla of diabetic rats. J. Diabetes Complications 12, 154–162.

    PubMed  CAS  Google Scholar 

  194. Ito, T., Nishimura, C., Takahashi, Y., Saito, T., and Omori, Y. (1997) The level of erythrocyte aldose reductase: a risk factor for diabetic neuropathy? Diabetes Res. Clin. Pract. 36, 161–167.

    PubMed  CAS  Google Scholar 

  195. Asano, T., Saito, Y., Kawakami, M., and Yamada, N. (2002) Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients. J. Diabetes Complications 16, 133–138.

    PubMed  Google Scholar 

  196. Hamada, Y., Nishimura, C., Koh, N., Sakakibara, F., Nakamura, J., Tanimoto, T., et al. (1998) Influence of interindividual variability of aldose reductase protein content on polyol-pathway metabolites and redox state in erythrocytes in diabetic patients. Diabetes Care 21, 1014–1018.

    PubMed  CAS  Google Scholar 

  197. Bravi, M. C., Pietrangeli, P., Laurenti, O., Basili, S., Cassone-Faldetta, M., Ferri, C., et al. (1997) Polyol pathway activation and glutathione redox status in non-insulin-dependent diabetic patients. Metabolism 46, 1194–1198.

    PubMed  CAS  Google Scholar 

  198. Hamada, Y., Odagaki, Y., Sakakibara, F., Naruse, K., Koh, N., and Hotta, N. (1995) Effects of an aldose reductase inhibitor on erythrocyte fructose 3-phosphate and sorbitol 3-phosphate levels in diabetic patients. Life Sci. 57, 23–29.

    PubMed  CAS  Google Scholar 

  199. Hamada, Y., Nakamura, J., Naruse, K., Komori, T., Kato, K., Kasuya, Y., et al. (2000) Epalrestat, an aldose reductase ihibitor, reduces the levels of Nepsilon-(carboxymethyl)lysine protein adducts and their precursors in erythrocytes from diabetic patients. Diabetes Care 23, 1539–1544.

    PubMed  CAS  Google Scholar 

  200. Vincent, T. E., Mendiratta, S. and May, J. M. (1999) Inhibition of aldose reductase in human erythrocytes by vitamin C. Diabetes Res. Clin. Pract. 43, 1–8.

    PubMed  CAS  Google Scholar 

  201. Wang, H., Zhang, Z. B., Wen, R. R., and Chen, J. W. (1995) Experimental and clinical studies on the reduction of erythrocyte sorbitol-glucose ratios by ascorbic acid in diabetes mellitus. Diabetes Res. Clin. Pract. 28, 1–8.

    PubMed  Google Scholar 

  202. Slatter, D. A., Bolton, C. H., and Bailey, A. J. (2000) The importance of lipid-derived malon-dialdehyde in diabetes mellitus. Diabetologia 43, 550–557.

    PubMed  CAS  Google Scholar 

  203. Jain, S. K. (1985) In vivo externalization of phosphatidylserine and phosphatidylethanol-amine in the membrane bilayer and hypercoagulability by the lipid peroxidation of erythrocytes in rats. J. Clin. Invest. 76, 281–286.

    PubMed  CAS  Google Scholar 

  204. Romero, M. J., Bosch-Morell, F., Romero, B., Rodrigo, J. M., Serra, M. A., and Romero, F. J. (1998) Serum malondialdehyde: possible use for the clinical management of chronic hepatitis C patients. Free Radic. Biol. Med. 25, 993–997.

    PubMed  CAS  Google Scholar 

  205. Muchova, J., Sustrova, M., Garaiova, I., Liptakova, A., Blazicek, P., Kvasnicka, P. Z., et al (2001) Influence of age on activities of antioxidant enzymes and lipid peroxidation products in erythrocytes and neutrophils of Down syndrome patients. Free Radic. Biol. Med. 31, 499–508.

    PubMed  CAS  Google Scholar 

  206. Marnett, L. J. (2002) Oxy radicals, lipid peroxidation and DNA damage. Toxicology 181–182, 219–222.

    PubMed  Google Scholar 

  207. Tuma, D. J. (2002) Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radic. Biol. Med. 32, 303–308.

    PubMed  CAS  Google Scholar 

  208. Dib, M., Garrel, C., Favier, A., Robin, V., and Desnuelle, C. (2002) Can malondialdehyde be used as a biological marker of progression in neurodegenerative disease? J. Neurol. 249, 367–374.

    PubMed  CAS  Google Scholar 

  209. Jain, S. K., Morshed, K. M., Kannan, K., Mcmartin, K. E., and Bocchini, J. A., Jr. (1996) Effect of elevated glucose concentrations on cellular lipid peroxidation and growth of cultured human kidney proximal tubule cells. Mol. Cell. Biochem. 162, 11–16.

    PubMed  CAS  Google Scholar 

  210. Rajeswari, P., Natarajan, R., Nadler, J. L., Kumar, D., and Kalra, V. K. (1991) Glucose induces lipid peroxidation and inactivation of membrane-associated ion-transport enzymes in human erythrocytes in vivo and in vitro. J. Cell. Physiol. 149, 100–109.

    PubMed  CAS  Google Scholar 

  211. Wittenstein, B., Klein, M., Finckh, B., Ullrich, K., and Kohlschutter, A. (2002) Plasma antioxidants in pediatric patients with glycogen storage disease, diabetes melltius, and hypercholesterolemia. Free Radic. Biol. Med. 33, 103–110.

    PubMed  CAS  Google Scholar 

  212. Olusi, S. O. (2002) Obesity is an independent risk factor for plasma lipid peroxidation and depletion of erythrocyte cytoprotectic enzymes in humans. Int. J. Obes. Relat. Metab. Disord. 26, 1159–1164.

    PubMed  CAS  Google Scholar 

  213. Jain, S. K. and Mcvie, R. (1999) Hyperketonemia can increase lipid peroxidation and lower glutathione levels in human erythrocytes in vitro and in type 1 diabetic patients. Diabetes 48, 1850–1855.

    PubMed  CAS  Google Scholar 

  214. Jain, S. K., Mcvie, R., Jackson, R., Levine, S. N., and Lim, G. (1999) Effect of hyperketonemia on plasma lipid peroxidation levels in diabetic patients. Diabetes Care 22, 1171–1175.

    PubMed  CAS  Google Scholar 

  215. Jain, S. K., Kannan, K., and Lim, G. (1998) Ketosis (acetoacetate) can generate oxygen radicals and cause increased lipid peroxidation and growth inhibition in human endothelial cells. Free Radic. Biol. Med. 25, 1083–1088.

    PubMed  CAS  Google Scholar 

  216. Schneider, C., Tallman, K. A., Porter, N. A., and Brash, A. R. (2001) Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals. J. Biol. Chem. 276, 20831–20838.

    PubMed  CAS  Google Scholar 

  217. Hoff, H. F., O'Neil, J., Wu, Z., Hoppe, G., and Salomon, R. L. (2003) Phospholipid hydroxyalkenals: biological and chemical properties of specific oxidized lipids present in atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 23, 275–282.

    PubMed  CAS  Google Scholar 

  218. Friguet, B. and Szweda, L. I. (1997) Inhibition of the multicatalytic proteinase by 4-hydroxy-2-nonenal cross-linked protein. FEBS Lett. 405, 21–25.

    PubMed  CAS  Google Scholar 

  219. Uchida, K., Shiraishi, M., Naito, Y., Torii, Y., Nakamura, Y., and Osawa, T. (1999) Activation of stress signaling pathways by the end product of lipid peroxidation 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J. Biol. Chem. 274, 2234–2242.

    PubMed  CAS  Google Scholar 

  220. Traverso, N., Menini, S., Odetti, P., Pronzato, M. A., Cottalasso, D., and Marinari, U. M. (2002) Diabetes impairs the enzymatic disposal of 4-hydroxynonenal in rat liver. Free Radic. Biol. Med. 32, 350–359.

    PubMed  CAS  Google Scholar 

  221. Yla-Herttuala, S., Palinski, W., Rosenfeld, M. E., Parthasarathy, S., Carew, T. E., Butler, S., Witztum, J. L., and Steinberg, D. (1989) Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J. Clin. Invest. 84, 1086–1095.

    PubMed  CAS  Google Scholar 

  222. Jurgens, G., Chen, Q., Esterbauer, H., Mair, S., Ledinski, G., and Dinges, H. P. (1993) Immunostaining of human autopsy aortas with antibodies to modified apolipoprotein B and apoprotein(a). Arterioscler. Thromb. 13, 1689–1699.

    PubMed  CAS  Google Scholar 

  223. Heinecke, J. W. (1998) Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidized low density lipoprotein hypothesis. Atherosclerosis. 141, 1–15.

    PubMed  CAS  Google Scholar 

  224. Seeds, M. C. and Bass, D. A. (1999) Regulation and metabolism of arachidonic acid. Clin. Rev. Allergy Immunol. 17, 5–26.

    PubMed  CAS  Google Scholar 

  225. Kalyankrishna, S., Parmentier, J. H., and Malik, K. U. (2002) Arachidonic acid-derived oxidation products initiate apoptosis in vascular smooth muscle cells. Prostaglandins Other Lipid Mediat. 70, 13–29.

    PubMed  CAS  Google Scholar 

  226. Nourooz-Zadeh, J., Tajaddini-Sarmadi, J., Mccarhty, S., Betteridge, D. J., and Wolff, S. P. (1995) Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes 44, 1054–1058.

    PubMed  CAS  Google Scholar 

  227. Santini, S. A., Marra, G., Giardina, B., Cotroneo, P., Mordente, A., Martorana, G. E., et al. (1997) Defective plasma antioxidant defenses and enhanced susceptibility to lipid peroxidation in uncomplicated IDDM. Diabetes 46, 1853–1858.

    PubMed  CAS  Google Scholar 

  228. Berg, T. J., Nourooz-Zadeh, J., Wolff, S. P., Tritschler, H. J., Bangstad, H. J., and Hanssen, K. F. (1998) Hydroperoxides in plasma are reduced by intensified insulin treatment: a randomized controlled study of IDDM patients with microalbuminuria. Diabetes Care 21, 1295–1300.

    PubMed  CAS  Google Scholar 

  229. Patricia, M. K., Kim, J. A., Harper, C. M., Shih, P. T., Berliner, J. A., Natarajan, R., et al. (1999) Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells. Arterioscler. Thromb. Vasc. Biol. 19, 2615–2622.

    PubMed  CAS  Google Scholar 

  230. Cyrus, T., Witztum, J. L., Rader, D. J., Tangirala, R., Fazio, S., Linton, M. F., et al. (1999) Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J. Clin. Invest. 103, 1597–1604.

    PubMed  CAS  Google Scholar 

  231. George, J., Afek, A., Shaish, A., Levkovitz, H., Bloom, N., Cyrus, T., et al. (2001) 12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice. Circulation 104, 1646–1650.

    PubMed  CAS  Google Scholar 

  232. Harats, D., Shaish, A., George, J., Mulkins, M., Kurihara, H., Levkovitz, H., et al. (2000) Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 20, 2100–2105.

    PubMed  CAS  Google Scholar 

  233. Shen, J., Herderick, E., Cornhill, J. F., Zsigmond, E., Kim, H. S., Kuhn, H., et al. (1996) Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J. Clin. Invest. 98, 2201–2208.

    PubMed  CAS  Google Scholar 

  234. Honda, H. M., Leitinger, N., Frankel M., Goldhaber, J. I., Natarajan, R., Nadler, J. L., et al. (1999) Induction of monocyte binding to endothelial cells by MM-LDL: role of lipoxygenase metabolites. Arterioscler. Thromb. Vasc. Biol. 19, 680–686.

    PubMed  CAS  Google Scholar 

  235. Morrow, J. D., Hill, K. E., Burk, R. F., Nammour, T. M., Badr, K. F., and Roberts, L. J. (1990) A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical mechanism. Proc. Natl. Acad. Sci. U. S. A. 87, 9383–9387.

    PubMed  CAS  Google Scholar 

  236. Morrow, J. D. and Roberts, L. J., (1996) F2-isoprostanes, prostaglandin-like products of lipid peroxidation, in Free Radicals: A Pratical Approach (Punchard, N. A. and Kelly, F. J., ed.). Oxford University Press: New York, pp. 147–157.

    Google Scholar 

  237. Morrow, J. D. and Roberts, L. J., II (1996) The isoprostanes. Current knowledge and directions for future research. Biochem. Pharmacol. 51, 1–9.

    PubMed  CAS  Google Scholar 

  238. Morrow, J. D. and Roberts, L. J. (1997) The isoprostanes: unique bioactive products of lipid peroxidation. Prog. Lipid Res. 36, 1–21.

    PubMed  CAS  Google Scholar 

  239. Roberts, L. J., II and Morrow, J. D. (1997) The generation and actions of isoprostanes. Biochim. Biophys. Acta 1345, 121–135.

    PubMed  CAS  Google Scholar 

  240. Kunapuli, P., Lawson, J. A., Rokach, J. A., Meinkoth, J. L., and Fitzgerald, G. A. (1998) Prostaglandin F2alpha (PGF2alpha) and the isoprostane 8,12-iso-isoprostane F2alpha-III induce cardiomyocyte hypertrophy. J. Biol. Chem. 273, 22442–22452.

    PubMed  CAS  Google Scholar 

  241. Zahler, S. and Becker, B. F. (1999) Indirect enhancement of neutrophil activity and adhesion to cultured human umbilical vein endothelial cells by isoprostanes (iPF2alpha-III and iPE2alpha-III). Prostaglandins Other Lipid Mediat. 57, 319–331.

    PubMed  CAS  Google Scholar 

  242. Yura, T., Fukunaga, M., Khan, R., Nassar, G. N., Badr, K. F., and Montero, A. (1990) Free-radical-generated F2-isoprostane stimulates cell proliferation and endothelin-1 expression on endothelial cells. Kidney Int. 56, 471–478.

    Google Scholar 

  243. Yin, K., Haluchka, P. V., Yan, Y. T., and Wong, P. Y.-K. (1994) Antiaggregatory activity of 8-epiprostaglandin F2alpha and other F-series prostanoids and their binding to thromboxane A2/prostaglandin H2 receptors in human platelets. J. Pharmacol Exp Therapeutics 270, 1192–1196.

    CAS  Google Scholar 

  244. Pratico, D., Smyth, E. M., Violi, F., and Fitzgerald, G. A. (1996) Local amplification of platelet function by 8-epi-prostaglandin F2alpha is not mediated by thromboxane receptor isoforms. J. Biol. Chem. 271, 14916–14924.

    PubMed  CAS  Google Scholar 

  245. Morrow, J. D., Minton, T. A., and Roberts, L. J. I. (1992) The F2-isoprostane, 8-epi-PGF2alpha, a potent agonist of the vascular thromboxane/endoperoxide receptor, is a platelet thromboxane/endoperoxide receptor antagonist. Prostaglandins 44, 155–163.

    PubMed  CAS  Google Scholar 

  246. Leitinger, N., Blazek, I., and Sinzinger, H. (1997) The influence of isoprostanes on ADP-induced platelet aggregation and cyclic AMP-generation in human platelets. Thromb. Res. 86, 337–342.

    PubMed  CAS  Google Scholar 

  247. Davi, G., Ciabattoni, G., Consoli, A., Mezzetti, A., Falco, A., Santarone, S., et al. (1999) In vivo formation of 8-iso-prostaglandin F2alpha and platelet activation in diabetes mellitus. Circulation 99, 224–229.

    PubMed  CAS  Google Scholar 

  248. Morrow, J. D., Minton, T. A., Mukundan, C. R., Campbell M. D., Zackert, W. E., Daniel, V. C., et al. (1994) Free radical-induced generation of isoprostances in vivo. J. Biol. Chem. 269, 4317–4326.

    PubMed  CAS  Google Scholar 

  249. Michoud, E., Lecomte, M., Lagarde, M., and Wiernsperger, N. (1998) In vivo effect of 8-epi-PGF2alpha on retinal circulation in diabetic and non-diabetic rats. Prostaglandins Leuko. Essent. Fatty Acids 59, 349–355.

    CAS  Google Scholar 

  250. Subbanagounder, G., Wong J. W., Lee, H., Faull, K. F., Miller, E., Witztum, J. L., et al. (2002) Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. Formation of these oxidized phospholipids in response to interleukin-1beta. J. Biol. Chem. 277, 7271–7281.

    PubMed  CAS  Google Scholar 

  251. Salomon, R. G., Batyreva, E., Kaur, K., Sprecher, D. L., Schreiber, M. J., Crabb, J. W., et al. (2000) Isolevuglandin-protein adducts in humans: products of free radical-induced lipid oxidation through the isoprostane pathway. Biochim. Biophys. Acta 1485 225–235.

    PubMed  CAS  Google Scholar 

  252. Salomon, R. G., Sha, W., Brame, C. J., Kaur, K., Subbanagounder, G., O'neil, J. et al. (1999). Protein adducts of Iso[4]levuglandin E2, a product of the isoprostane pathway, in oxidized low density lipoprotein. J. Biol. Chem. 274, 20271–20280.

    PubMed  CAS  Google Scholar 

  253. Roberts, L. J. I., Salomon, R. G., Morrow J. D., and Brame, C. J. (1999) New developments in the isoprostane pathway: identification of novel highly reactive gamma-ketoaldehydes (isolevuglandins) and characterization of their protein adducts. FASEB J. 13, 1157–1168.

    PubMed  CAS  Google Scholar 

  254. Brame, C. J., Salomon, R. G., Morrow J. D., and Roberts, L. G. I. (1999) Identification of extremely reactive gamma-ketoaldehydes (isolevuglandins) as products of the isoprostane pathway and characterization of their lysyl protein adducts. J. Biol. Chem. 274, 13139–13146.

    PubMed  CAS  Google Scholar 

  255. Bachi, A., Zuccato, E., Baraldi M., Fanelli, R., and Chabrando, C. (1996) Measurement of urinary 8-epi-prostaglandin F2alpha, a novel index of lipid peroxidation in vivo, by immunoaffinity extraction/gas chromatography-mass spoectrometry. Basal levels in smokers and non-smokers. Free Radic. Biol. Med. 20, 619–624.

    PubMed  CAS  Google Scholar 

  256. Morrow, J. D., Awad, J. A., Boss, H. J., Blair, I. A., and Roberts, L. J. I. (1992) Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids. Proc. Natl. Acad. Sci. USA 89, 10721–10725.

    PubMed  CAS  Google Scholar 

  257. Patrono, C. and Fitzgerald, G. A. (1997) Isoprostanes: potential markers of oxidant stress in atherothrombotic disease. Arterioscler. Thromb. Vasc. Biol. 17, 2309–2315.

    PubMed  CAS  Google Scholar 

  258. Mehrabi, M. R., Ekonekcioglu, C., Tatzber, F., Oguogho, A., Ullrich, R., Morgan, A., et al. (1999) The isoprostane 8-epi-PGF2alpha is accumulated in coronary arteries isolated from patients with coronary heart disease. Cardiovasc. Res. 43, 492–499.

    PubMed  CAS  Google Scholar 

  259. Kauffman, L. D., Sokol R. J., Jones, R. H., Awad, J. A., Rewers M. J., and Norris, J. M. (2003) Urinary F2-isoprostanes in young healthy children at risk for type 1 diabetes mellitus. Free Radic. Biol. Med. 35, 551–557.

    PubMed  CAS  Google Scholar 

  260. Gopaul, N. K., Angglard, E. E., Mallet, A. I., Betteridge, D. J., Wolff, S. P., and Nourooz-Zadeh, J. (1995) Plasma 8-epi-PGF2alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Lett. 368, 225–229.

    PubMed  CAS  Google Scholar 

  261. Palmer, A. M., Thomas, C. R., Gopaul, N., Dhir, S., Anggard, E. E., Poston, L., et al. (1998) Dietary antioxidant supplementation reduces lipid peroxidation but impairs vascular function in small mesenteric arteries of the streptozotocin-diabetic rat. Diabetologia 41, 148–156.

    PubMed  CAS  Google Scholar 

  262. Devaraj, S., Hirany, S. V., Burk, R. F., and Jialal, I. (2001) Divergence between LDL oxidative susceptibility and urinary F(2)-isoprostanes as measures of oxidative stress in type 2 diabetes. Clin. Chem. 47, 1974–1979.

    PubMed  CAS  Google Scholar 

  263. Voutilainen, S., Morrow, J. D., Roberts, L. J. I., Alfthan, G., Alho, H., Nyyssonen, K., t al. (1999) Enhanced in vivo lipid peroxidation at elevated plasma total homocysteine levels. Arterioscler. Thromb. Vasc. Biol. 19, 1263–1266.

    PubMed  CAS  Google Scholar 

  264. Refsum, H., Smith, A. D., Ueland, P. M., Nexo, E., Clarke, R., Mcpartlin, J., et al. (2004) Facts and recommendations about total homocysteine determinations: an expert opinion. Clin. Chem. 50, 3–32.

    PubMed  CAS  Google Scholar 

  265. Suzuki, D. and Miyata, T. (1999) Carbonyl stress in the pathogenesis of diabetic nephropathy. Intern. Med. 38, 309–314.

    PubMed  CAS  Google Scholar 

  266. Jain, A. K., Lim, G., Langford, M. and Jain, S. K. (2002) Effect of high-glucose levels on protein oxidation in cultured lens cells, and in crystalline and albumin solution and its inhibition by vitamin B(6) and N-acetylcysteine: its possible relevance to cataract formation in diabetes. Free Radic. Biol. Med. 33, 1615–1621.

    PubMed  CAS  Google Scholar 

  267. Portero-Otin, M., Pamplona, R., Ruiz, M. C., Cabiscol, E., Prat, J., and Bellmunt, M. J. (1999) Diabetes induces an impairment in the proteolytic activity against oxidized proteins an a hetergeneous effect in nonenzymatic protein modifications in the cytosol of rat liver and kidney. Diabetes 48, 2215–2220.

    PubMed  CAS  Google Scholar 

  268. Oh-Ishi, M., Ueno, T., and Maeda, T. (2003) Proteomic method detects oxidatively induced protein carbonyls in muscles of a diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Free Radic. Biol. Med. 34, 11–22.

    PubMed  CAS  Google Scholar 

  269. Shringarpure, R. and Davies, K. J. A. (2002) Protein turnover by the proteasome in aging and disease. Free Radic. Biol. Med. 32, 1084–89.

    PubMed  CAS  Google Scholar 

  270. Friguet, B., Szweda, L. I., and Stadtman, E. R. (1994) Susceptibility of glucose-6-phosphate dehydrogenase modified by 4-hydroxy-2-nonenal and metal-catalyzed oxidation to proteolysis by the multicatalytic protease. Arch. Biochem. Biophys. 311, 168–173.

    PubMed  CAS  Google Scholar 

  271. Brownlee, M. (1995) Advanced protein glycosylation in diabetes and aging. Annu. Rev. Med. 46, 223–234.

    PubMed  CAS  Google Scholar 

  272. Bolli, G., Compagnucci, P., Cartechini, M. G., Santeusanio, F., Cirotto, C., Scionti, L., et al. (1980) Hb A1 in subjects with abnormal glucose tolerance but normal fasting plasma glucose. Diabetes 29, 272–277.

    PubMed  CAS  Google Scholar 

  273. Sensi, M., Pricci, F., Andreani, D., and Di Mario, U. (1991) Advanced nonenzymatic glycation endproducts (AGE): their relevance to aging and the pathogenesis of late diabetic complications. Diabetes Res. 16, 1–9.

    PubMed  CAS  Google Scholar 

  274. Bucala, R., Makita, Z., Koschinsky, T., Cerami, A., and Vlassara, H. (1993) Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc. Natl. Acad. Sci. U.S.A. 90, 6434–6438.

    PubMed  CAS  Google Scholar 

  275. Reddy, S., Bichler, J., Wells-Knecht, K. J., Thorpe, S. R., and Baynes, J. W. (1995) N epsilon-(carboxymethyl)lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry 34, 10872–10878.

    PubMed  CAS  Google Scholar 

  276. Singh, R., Barden, A., Mori, T., and Beilin, L. (2001) Advanced glycation end-products: a review. Diabetologia 44, 129–146.

    PubMed  CAS  Google Scholar 

  277. Ghitescu, L. D., Gugliucci, A., and Dumas, F. (2001) Actin and annexins I and II are among the main endothelial plasmalemma-associated proteins forming early glucose adducts in experimental diabetes. Diabetes 50, 1666–1674.

    PubMed  CAS  Google Scholar 

  278. Uchimura, T., Nakano, K., Hashiguchi, T., Iwamoto, H., Miura, K., Yoshimura, Y., et al. (2001) Elevation of N-(carboxymethyl)valine residue in hemoglobin of diabetic patients. Its role in the development of diabetic nephropathy. Diabetes Care 24, 891–896.

    PubMed  CAS  Google Scholar 

  279. Wolffenbuttel, B. H., Giordano, D., Founds, H. W., and Bucala, R. (1996) Long-term assessment of glucose control by haemoglobin-AGE measurement. Lancet 347, 513–515.

    PubMed  CAS  Google Scholar 

  280. Yan, H. and Harding, J. J. (1997) Glycation-induced inactivation and loss of antigenicity of catalase and superoxide dismutase. Biochem. J. 328, 599–605.

    PubMed  CAS  Google Scholar 

  281. Ando, K., Beppu, M., Kikugawa, K., Nagai, R., and Horiuchi, S. (1999) Membrane proteins of human erythrocytes are modified by advanced glycation and products during aging in the circulation. Biochem. Biophys. Res. Commun. 258, 123–127.

    PubMed  CAS  Google Scholar 

  282. Gonzalez Flecha, F. L., Castello, P. R., Caride, A. J., Gagliardino, J. J., and Rossi, J. P. (1993) The erythrocyte calcium pump is inhibited by non-enzymic glycation: studies in situ and with the purified enzyme. Biochem. J. 29, 369–375.

    Google Scholar 

  283. Chellan, P. and Nagaraj, R. H. (2001) Early glycation products produce pentosidine crosslinks on native proteins. novel mechanism of pentosidine formation and propagation of glycation. J. Biol. Chem. 276, 3895–3903.

    PubMed  CAS  Google Scholar 

  284. Jain, S. K. and Palmer, M. (1997) The effect of oxygen radicals metabolites and vitamin E on glycosylation of proteins. Free Radic. Biol. Med. 22, 593–596.

    PubMed  CAS  Google Scholar 

  285. Ortwerth, B. J., James, H., Simpson, G., and Linetsky, M. (1998) The generation of superoxide anions in glycation reactions with sugars, osones, and 3-deoxyosones. Biochem. Biophys. Res. Commun. 245, 161–165.

    PubMed  CAS  Google Scholar 

  286. Akagawa, M., Sasaki, T., and Suyama, K. (2002) Oxidative deamination of lysine residue in plasma protein of diabetic rats. Novel mechanism via the Maillard reaction. Eur. J. Biochem. 269, 5451–5458.

    PubMed  CAS  Google Scholar 

  287. Qian, M. and Eaton, J. W. (2000) Glycochelates and the etiology of diabetic peripheral neuropathy. Free Radic. Biol. Med. 28, 652–656.

    PubMed  CAS  Google Scholar 

  288. Bulteau, A.-L., Verbeke, P., Petropoulos, I., Chaffotte, A.-F., and Frigue, B. (2001) Proteasome inhibition in glyoxal-treated fibroblasts an resistance of glycated glucose-6-phosphate dehydrogenase to 20 S proteasome degradation in vitro. J. Biol. Chem. 276, 45662–45668.

    PubMed  CAS  Google Scholar 

  289. Ling, X., Nagai, R., Sakashita, N., Takeya, M., Horiuchi, S., and Takahashi, K. (2001) Immunohistochemical distribution and quantitative biochemical detection of advanced glycation end products in fetal to adult rats and in rats with streptozotocin-induced diabetes. Lab. Invest. 81, 845–861.

    PubMed  CAS  Google Scholar 

  290. Candiloros, H., Muller, S., Ziegler, O., Donner, M., and Drouin, P. (1996) Role of albumin glycation on the erythrocyte aggregation: an in vitro study. Diabetes Med. 13, 646–650.

    CAS  Google Scholar 

  291. Niwa, T., Katsuzaki, T., Miyazaki, S., Miyazaki, T., Ishizaki, Y., Hayase, F., et al. (1997) Immunohistochemical detection of imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients. J. Clin. Invest. 99, 1272–1280.

    PubMed  CAS  Google Scholar 

  292. Booth, A. A., Khalifah, R. G., and Hudson, B. G. (1996) Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine. Biochem. Biophys. Res. Commun. 220, 113–119.

    PubMed  CAS  Google Scholar 

  293. Metz, T. O., Alderson, N. L., Chachich, M. E., Thorpe, S. R., and Baynes, J. W. (2003) Pyridoxamine traps intermediates in lipid peroxidation reactions in vivo: evidence on the role of lipids in chemical modification of protein and development of diabetic complications. J. Biol. Chem. 278, 42012–42019.

    PubMed  CAS  Google Scholar 

  294. Stitt, A., Gardiner, T. A., Anderson, N. L., Canning, P., Frizzell, N., Duffy, N., et al. (2002) The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes 51, 2826–2832.

    PubMed  CAS  Google Scholar 

  295. Nagaraj, R. H., Sarkar, P., Mally, A., Biemel, K. M., Lederer, M. O., and Padayatti, P. S. (2002) Effect of pyridoxamine on chemical modification of proteins by carbonyls in diabetic rats: characterization of a major product from the reaction of pyridoxamine and methylglyoxal. Arch. Biochem. Biophys. 402, 110–119.

    PubMed  CAS  Google Scholar 

  296. Voziyan, P. A., Metz, T. O., Baynes, J. W., and Hudson, B. G. (2002) A post-Amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation. J. Biol. Chem. 277, 3397–3403.

    PubMed  CAS  Google Scholar 

  297. Giardino, I., Fard, A. K., Hatchell, D. L., and Brownlee, M. (1998) Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation, and oxidant-induced apoptosis. Diabetes 47, 1114–1120.

    PubMed  CAS  Google Scholar 

  298. Ihm, S. H., Yoo, H. J., Park, S. W., and Ihm, J. (1999) Effect of aminoguanidine on lipid peroxidation in streptozotocin-induced diabetic rats. Metabolism 48, 1141–1145.

    PubMed  CAS  Google Scholar 

  299. Jakus, V., Hrnciarova, M., Carsky, J., Krahulec, B., and Rietbrock, N. (1999) Inhibition of nonenzymatic protein glycation and lipid peroxidation by drugs with antioxidant activity. Life Sci. 65, 1991–1993.

    PubMed  CAS  Google Scholar 

  300. Kedziora-Kornatowska, K. Z., Luciak, M., Blaszcyk, J., and Pawlak, W. (1998) Effect of aminoguanidine on erythrocyte lipid peroxidation and activities of antioxidant enzymes in experimental diabetes. Clin. Chem. Lab. Med. 36, 771–775.

    PubMed  CAS  Google Scholar 

  301. Ha, H. and Lee, H. B. (2000) Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucose. Kidney Int. Suppl. 77, S19-S25.

    PubMed  CAS  Google Scholar 

  302. Salahudeen, A. K., Kanji, V., Reckelhoff, J. F., and Schmidt, A. M. (1997) Pathogenesis of diabetic nephropathy: a radical approach. Nephrol. Dial. Transplant. 12, 664–668.

    PubMed  CAS  Google Scholar 

  303. Wautier, J. L., Wautier, M. P., Schmidt, A. M., Anderson, G. M., Hori, O., Zoukourian, C., Capron, L., Chappey, O., Yan, S. D., Brett, J., et al. (1994) Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc. Natl. Acad. Sci. USA 91, 7742–7746.

    PubMed  CAS  Google Scholar 

  304. Schmidt, A. M., Hori, O., Brett, J., Yan, S. D., Wautier, J. L., and Stern, D. (1994) Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler. Thromb. 14, 1521–1528.

    PubMed  CAS  Google Scholar 

  305. Assero, G., Lupo, G., Anfuso, C. D., Ragusa, N., and Alberghina, M. (2001) High glucose and advanced glycation end products induce phospholipid hydrolysis and phospholipid enzyme inhibition in bovine retinal pericytes. Biochim. Biophys. Acta 1533, 128–140.

    PubMed  CAS  Google Scholar 

  306. Wautier, M. P., Chappey, O., Corda, S., Stern, D. M., Schmidt, A. M., and Wautier, J. L. (2001) Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am. J. Physiol. Endocrinol. Metab. 280, E685-E6894.

    PubMed  CAS  Google Scholar 

  307. Yan, S. D., Schmidt, A. M., Anderson, G. M., Zhang, J., Brett, J., Zou, Y. S., et al. (1994) Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J. Biol. Chem. 269, 9889–9897.

    PubMed  CAS  Google Scholar 

  308. Schmidt, A. M., Yan, S. D., Yan, S. F., and Stern, D. M. (2000) The biology of the receptor for advanced glycation end products and its ligands. Biochim. Biophys. Acta 1498, 99–111.

    PubMed  CAS  Google Scholar 

  309. Bierhaus, A., Chevion, S., Chevion, M., Hofmann, M., Quehenberger, P., Illmer, T., et al. (1997) Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46, 1481–1490.

    PubMed  CAS  Google Scholar 

  310. Valencia, J. V., Mone, M., Zhang, J., Weetall, M., Buxton, F. P., and Hughes, T. E. (2004) Divergent pathways of gene expression are activated by the RAGE ligands S100b and AGE-BSA. Diabetes 53, 743–751.

    PubMed  CAS  Google Scholar 

  311. Park, L., Raman, K. G., Lee, K. J., Lu, Y., Ferran, L. J., Jr., Chow, W. S., et al. (1998) Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation end-products. Nat. Med. 4, 1025–1031.

    PubMed  CAS  Google Scholar 

  312. Ramstrom, S., Ranby, M., and Lindahl, T. L. (2003) Platelet phosphatidylserine exposure and procoagulant activity in clotting whole blood—different effects of collagen, TRAP and calcium ionophore A23187. Thromb. Haemost. 89, 132–141.

    PubMed  CAS  Google Scholar 

  313. Schlegel, R. A., Prendergast, T. W., and Williamson, P. (1985) Membrane phospholipid asymmetry as a factor in erythrocyte-endothelial cell interactions, J. Cell. Physiol. 123, 215–218.

    PubMed  CAS  Google Scholar 

  314. Manodori, A. B., Barabino, G. A., Lubin, B. H., and Kuypers, F. A. (2000) Adherence of phosphatidylserine-exposing erythrocytes to endothelial matrix thrombospondin. Blood 95, 1293–1300.

    PubMed  CAS  Google Scholar 

  315. Fadok, V. A., Bratton, D. L., Rose, D. M., Pearson, A., Ezekewitz, R. A., and Henson, P. M. (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90.

    PubMed  CAS  Google Scholar 

  316. Wali, R. K., Jaffe, S., Kumar, D., and Kalra, V. K. (1988) Alterations in organization of phospholipids in erythrocytes as factor in adherence to endothelial cells in diabetes mellitus. Diabetes 37, 104–111.

    PubMed  CAS  Google Scholar 

  317. Wilson, M. J., Richter-Lowney, K., and Daleke, D. L. (1993) Hyperglycemia induces a loss of phospholipid asymmetry in human erythrocytes. Biochemistry 32, 11302–11310.

    PubMed  CAS  Google Scholar 

  318. Wautier, J. L., Paton, R. C., Wautier, M. P., Pintigny, D., Abadie, E., Passa, P., et al. (1981) Increased adhesion of erythrocytes to endothelial cells in diabetes mellitus and its relation to vascular complications. N. Engl. J. Med. 305, 237–242.

    Article  PubMed  CAS  Google Scholar 

  319. Ceriello, A., Giacomello, R., Stel, G., Motz, E., Taboga, C., Tonutti, L., et al. (1995) Hyperglycemia-induced thrombin formation in diabetes. The possible role of oxidative stress. Diabetes 44, 924–928.

    PubMed  CAS  Google Scholar 

  320. Tyurina, Y. Y., Serinkan, F. B., Tyurin, V. A., Kini, V., Yalowich, J. C., Schroit, A. J., et al. (2004) Lipid antioxidant, etoposide, inhibits phosphatidylserine externalization and macrophage clearance of apoptotic cells by preventing phosphatidylserine oxidation. J. Biol. Chem. 279, 6056–6064.

    PubMed  CAS  Google Scholar 

  321. Weinstein, E. A., Li, H., Lawson, J. A., Rokach, J., Fitzgerald, G. A., and Axelsen, P. H. (2000) Prothrombinase acceleration by oxidatively damaged phospholipids. J. Biol. Chem. 275, 22925–22930.

    PubMed  CAS  Google Scholar 

  322. Balasubramanian, K., Bevers, E. M., Willems, G. M., and Schroit, A. J. (2001) Binding of annexin V to membrane products of lipid peroxidation. Biochemistry 40, 8672–8676.

    PubMed  CAS  Google Scholar 

  323. Middlekoop, E., Van Der Hoek, E. E., Bevers, E. M., Comfurius, P., Slotboom, A. J., Op Den Kamp, J. A., et al. (1989) Involvement of ATP-dependent aminophospholipid translocation in maintaining phospholipid asymmetry in diamide-treated human erythrocytes. Biochim. Biophys. Acta 981, 151–160.

    PubMed  CAS  Google Scholar 

  324. Kamp, D., Sieberg, T., and Haest, C. W. (2001) Inhibition and stimulation of phospholipid scrambling activity. Consequences for lipid asymmetry, echinocytosis, and microvesiculation of erythrocytes. Biochemistry 40, 9438–9446.

    PubMed  CAS  Google Scholar 

  325. Newton, A. C. (1995) Protein kinase C: structure, function, and rugulation. J. Biol. Chem. 270, 28495–28498.

    PubMed  CAS  Google Scholar 

  326. Newton, A. C. (1996) Protein kinase C: ports of anchor in the cell. Curr. Biol. 6, 806–809.

    PubMed  CAS  Google Scholar 

  327. Koya, D. and King, G. L. (1998) Protein kinase C activation and the development of diabetic complications. Diabetes 47, 859–866.

    PubMed  CAS  Google Scholar 

  328. Lynch, J. J., Ferro, T. J., Blumenstock, F. A., Brockenauer, A. M., and Malik, A. B. (1990) Increased endothelial albumin permeability mediated by protein kinase C activation. J. Clin. Invest. 85, 1991–1998.

    PubMed  CAS  Google Scholar 

  329. Rasmussen, H., Forder, J., Kojima, I., and Scriabine, A. (1984) TPA-induced contraction of isolated rabbit vascular smooth muscle. Biochem. Biophys. Res. Commun. 122, 776–784.

    PubMed  CAS  Google Scholar 

  330. Inoguchi, T., Battan, R., Handler, E., Sportsman, J. R., Heath, W., and King, G. L. (1992) Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc. Natl. Acad. Sci. USA 89, 11059–11063.

    PubMed  CAS  Google Scholar 

  331. Abiko, T., Abiko, A., Clermont, A. C., Shoelson, B., Horio, N., Takahashi, J., et al. (2003) Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation. Diabetes 52, 829–837.

    PubMed  CAS  Google Scholar 

  332. Venugopal, S. K., Devaraj, S., Yang, T., and Jialal, I. (2002) α-Tocopherol decreases superoxide anion release in human monocytes under hyperglycemic conditions via inhibition of protein kinase C-alpha. Diabetes 51, 3049–3054.

    PubMed  CAS  Google Scholar 

  333. Craven, P. A., Davidson, C. M., and Derubertis, F. R. (1990) Increase in diacylglycerol mass in isolated glomeruli by glucose from de novo synthesis of glycerolipids. Diabetes 39, 667–674.

    PubMed  CAS  Google Scholar 

  334. Craven, P. A. and Derubertis, F. R. (1989) Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. Possible mediation by glucose. J. Clin. Invest. 83, 1667–1675.

    PubMed  CAS  Google Scholar 

  335. Koya, D., Lee, I. K., Ishii, H., Kanoh, H., and King, G. L. (1997) Prevention of glomerular dysfunction in diabetic rats by treatment with d-alpha-tocopherol. J. Am. Soc. Nephrol., 8, 426–435.

    PubMed  CAS  Google Scholar 

  336. Kunisaki, M., Bursell, S. E., Clermont, A. C., Ishii, H., Ballas, L. M., Jirousek, M. R., et al. (1995) Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. Am. J. Physiol. 269, E239-E246.

    PubMed  CAS  Google Scholar 

  337. Shiba, T., Inoguchi, T., Sportsman, J. R., Heath, W. F., Bursell, S., and King, G. L. (1993) Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am. J. Physiol. 265, E783-E793.

    PubMed  CAS  Google Scholar 

  338. Ishii, H., Jirousek, M. R., Koya, D., Takagi, C., Xia, P., Clermont, A., et al. (1996) Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 272, 728–731.

    PubMed  CAS  Google Scholar 

  339. Igarashi, M., Wakasaki, H., Takahara, N., Ishii, H., Jiang, Z. Y., Yamauchi, T., et al. (1999) Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J. Clin. Invest. 103, 185–195.

    Article  PubMed  CAS  Google Scholar 

  340. Pricci, F., Leto, G., Amadio, L., Iacobini, C., Cordone, S., Catalano, S., et al. (2003) Oxidative stress in diabetes-induced endothelial dysfunction involvement of nitric oxide and protein kinase C. Free Radic. Biol. Med. 35, 683–694.

    PubMed  CAS  Google Scholar 

  341. Morigi, M., Angioletti, S., Imberti, B., Donadelli, R., Micheletti, G., Figliuzzi, M., et al. (1998) Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. J. Clin. Invest. 101, 1905–1915.

    PubMed  CAS  Google Scholar 

  342. Lenardo, M. J. and Baltimore, D. (1989) NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 58, 227–229.

    PubMed  CAS  Google Scholar 

  343. Beyaert, R. (2003) Nuclear Factor kB: Regulation and Role in Disease. Kluwer Academic Publishers, Dordrecht.

    Google Scholar 

  344. Evans, J. L., Goldfine, I. D., Maddux, B. A., and Grodsky, G. M. (2002) Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr. Rev. 23, 599–622.

    PubMed  CAS  Google Scholar 

  345. Pieper, G. M. and Riaz Ul, H. (1997) Activation of nuclear factor-kappaB in cultured endothelial cells by increased glucose concentration: prevention by calphostin C. J. Cardiovasc. Pharmacol. 30, 528–532.

    PubMed  CAS  Google Scholar 

  346. Du, X., Stocklauser-Farber, K., and Rosen, P. (1999) Generation of reactive oxygen intermediates, activation of NF-kappaB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radic. Biol. Med. 27, 752–763.

    PubMed  CAS  Google Scholar 

  347. Brand, K., Page, S., Rogler, G., Bartsch, A., Brandl, R., Knuechel, R., et al. (1996) Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J. Clin. Invest. 97, 1715–1722.

    PubMed  CAS  Google Scholar 

  348. Chen, Z., Gibson, T. B., Robinson, F., Silvestro, L., Pearson, G., Xu, B., et al. (2001) MAP kinases. Chem. Rev. 101, 2449–2476.

    PubMed  CAS  Google Scholar 

  349. Davis, R. J. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252.

    PubMed  CAS  Google Scholar 

  350. Minden, A. and Karin, M. (1997) Regulation and function of the JNK subgroup of MAP kinases. Biochim. Biophys. Acta 1333, F85-F104.

    PubMed  CAS  Google Scholar 

  351. Nebreda, A. R. and Porras, A. (2000) p38 MAP kinases: beyond the stress response. Trends Biochem. Sci. 25, 257–260.

    PubMed  CAS  Google Scholar 

  352. Kumar, S., Boehm, J., and Lee, J. C. (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat. Rev. Drug Discov. 2, 717–726.

    PubMed  CAS  Google Scholar 

  353. Fujita, H., Omori, S., Ishikura, K., Hida, M., and Awazu, M. (2004) ERK and p38 mediate high-glucose-induced hypertrophy and TGF-beta expression in renal tubular cells. Am. J. Physiol. Renal Physiol. 286, F120-F126.

    PubMed  CAS  Google Scholar 

  354. Liu, B. F., Miyata, S., Hirota, Y., Higo, S., Miyazaki, H., Fukunaga, M., et al. (2003) Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells. Kidney Int. 63, 947–957.

    PubMed  CAS  Google Scholar 

  355. Price, S. A., Agthong, S., Middlemas, A. B., and Tomlinson, D. R. (2004) Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy: interactions with aldose reductase. Diabetes 53, 1851–1856.

    PubMed  CAS  Google Scholar 

  356. Koistinen, H. A., Chibalin, A. V., and Zierath, J. R. (2003) Aberrant p38 mitogen-activated protein kinase signalling in skeletal muscle from type 2 diabetic patients. Diabetologia 46, 1324–1328.

    PubMed  CAS  Google Scholar 

  357. Carlson, C. J., Koterski, S., Sciotti, R. J., Poccard, G. B., and Rondinone, C. M. (2003) Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Diabetes 52, 634–641.

    PubMed  CAS  Google Scholar 

  358. Coulon, L., Calzada, C., Moulin, P., Vericel, E., and Lagarde, M. (2003) Activation of p38 mitogen-activated protein kinase/cytosolic phospholipase A2 cascade in hydroperoxide-stressed platelets. Free Radic. Biol. Med. 35, 616–625.

    PubMed  CAS  Google Scholar 

  359. Gum, R. J., Gaede, L. L., Heindel, M. A., Waring, J. F., Trevillyan, J. M., Zinkerr, B. A., et al. (2003) Antisense protein tyrosine phosphatase 1B reverses activation of p38 mitogen-activated protein kinase in liver of ob/ob mice. Mol. Endocrinol. 17, 1131–1143.

    PubMed  CAS  Google Scholar 

  360. Agthong, S. and Tomlinson, D. R. (2002) Inhibition of p38 MAP kinase corrects biochemical and neurological deficits in experimental diabetic neuropathy. Ann. N. Y. Acad. Sci. 973, 359–362.

    Article  PubMed  CAS  Google Scholar 

  361. Hirosumi, J., Tuncman, G., Chang, L., Gorgun, C. Z., Uysal, K. T., Maeda, K., et al. (2002) A central role for JNK in obesity and insulin resistance. Nature 420, 333–336.

    PubMed  CAS  Google Scholar 

  362. Li, M., Mossman, B. T., Kolpa, E., Timblin, C. R., Shukla, A., Taatjes, D. J., et al. (2003) Age-related differences in MAP kinase activity in VSMC in response to glucose or TNF-alpha. J. Cell. Physiol. 197, 418–425.

    PubMed  CAS  Google Scholar 

  363. Green, D. R. (1998) Apoptotic pathways: the roads to ruin. Cell 94, 695–698.

    PubMed  CAS  Google Scholar 

  364. Cohen, G. M. (1997) Caspases: the executioners of apoptosis. Biochem. J. 326, 1–16.

    PubMed  CAS  Google Scholar 

  365. Nagata, S. (1997) Apoptosis by death factor. Cell 88, 355–365.

    PubMed  CAS  Google Scholar 

  366. Thornberry, N. A. and Lazebnik, Y. (1998) Caspases: enemies within. Science 281, 1312–1316.

    PubMed  CAS  Google Scholar 

  367. Vincent, A. M., Brownlee, M., and Russell, J. W. (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann. N. Y. Acad. Sci. 959, 368–383.

    Article  PubMed  CAS  Google Scholar 

  368. Greene, D. A., Stevens, M. J., Obrosova, I., and Feldman, E. L. (1999) Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy. Eur. J. Pharmacol. 375, 217–223.

    PubMed  CAS  Google Scholar 

  369. Sima, A. A. (2003) New insights into the metabolic and molecular basis for diabetic neuropathy. Cell. Mol. Life Sci. 60, 2445–2464.

    PubMed  CAS  Google Scholar 

  370. Cai, L., Li, W., Wang, G., Guo, L., Jiang, Y., and Kang, Y. J. (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51, 1938–1948.

    PubMed  CAS  Google Scholar 

  371. Srinivasan, S., Stevens, M., and Wiley, J. W. (2000) Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. Diabetes 49, 1932–1938.

    PubMed  CAS  Google Scholar 

  372. Cheng, C. and Zochodne, D. W. (2003) Sensory neurons with activated caspase-3 survive long-term experimental diabetes. Diabetes 52, 2363–2371.

    PubMed  CAS  Google Scholar 

  373. Ido, Y., Carling, D., and Ruderman, N. (2002) Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes 51, 159–167.

    PubMed  CAS  Google Scholar 

  374. Russell, J. W., Sullivan, K. A., Windebank, A. J., Herrmann, D. N., and Feldman, E. L. (1999) Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol. Dis. 6, 347–363.

    PubMed  CAS  Google Scholar 

  375. Schmeichel, A. M., Schmelzer, J. D., and Low, P. A. (2003) Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. Diabetes 52, 165–171.

    PubMed  CAS  Google Scholar 

  376. Wu, Q. D., Wang, J. H., Fennessy, F., Redmond, H. P., and Bouchier-Hayes, D. (1999) Taurine prevents high-glucose-induced human vascular endothelial cell apoptosis. Am. J. Physiol. 277, C1229-C1238.

    PubMed  CAS  Google Scholar 

  377. Dubois, R. N., Abramson, S. B., Crofford, L., Gupta, R. A., Simon, L. S., Van De Putte, L. B., et al. (1998) Cyclooxygenase in biology and disease. FASEB J. 12, 1063–1073.

    PubMed  CAS  Google Scholar 

  378. Feng, L., Xia, Y., Garcia, G. E., Hwang, D., and Wilson, C. B. (1995) Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide. J. Clin. Invest. 95, 1669–1675.

    PubMed  CAS  Google Scholar 

  379. Pop-Busui, R., Marinescu, V., Van Huysen, C., Li, F., Sullivan, K., Greene, D. A., et al. (2002) Dissection of metabolic, vascular, and nerve conduction interrelationships in experimental diabetic neuropathy by cyclooxygenase inhibition and acetyl-L-carnitine administration. Diabetes 51, 2619–2628.

    PubMed  CAS  Google Scholar 

  380. Quilley, J. and Chen, Y. J. (2003) Role of COX-2 in the enhanced vasoconstrictor effect of arachidonic acid in the diabetic rat kidney. Hypertension 42, 837–843.

    PubMed  CAS  Google Scholar 

  381. Nasrallah, R., Landry, A., Singh, S., Sklepowicz, M., and Hebert, R. L. (2003) Increased expression of cyclooxygenase-1 and-2 in the diabetic rat renal medulla. Am. J. Physiol. Renal Physiol. 285, F1068-F1077.

    PubMed  CAS  Google Scholar 

  382. Shanmugam, N., Gaw Gonzalo, I. T., and Natarajan, R. (2004) Molecular mechanisms of high glucose-induce cyclooxygenase-2 expression in monocytes. Diabetes 53, 795–802.

    PubMed  CAS  Google Scholar 

  383. Kiritoshi, S., Nishikawa, T., Sonoda, K., Kukidome, D., Senokuchi, T., Matsuo, T., et al. (2003) Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. Diabetes 52, 2570–2577.

    PubMed  CAS  Google Scholar 

  384. Cipollone, F., Iezzi, A., Fazia, M., Zucchelli, M., Pini, B., Cuccurullo, C., et al. (2003) The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation 108, 1070–1077.

    PubMed  CAS  Google Scholar 

  385. Sennlaub, F., Valamanesh, F., Vazquez-Tello, A., El-Asrar, A. M., Checchin, D., Brault, S., et al. (2003) Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy. Circulation 108, 198–204.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David L. Daleke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Niedowicz, D.M., Daleke, D.L. The role of oxidative stress in diabetic complications. Cell Biochem Biophys 43, 289–330 (2005). https://doi.org/10.1385/CBB:43:2:289

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/CBB:43:2:289

Index Entries

Navigation