Poly(ADP-Ribose) Polymerase Activation and Nitrosative Stress in the Development of Cardiovascular Disease in Diabetes

  • Pál Pacher
  • Csaba Szabó
Part of the Contemporary Cardiology book series (CONCARD)


Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus (DM). Diabetic vascular dysfunction is a major clinical problem, which underlies the development of various severe complications including retinopathy, nephropathy, neuropathy, and increase the risk of stroke, hypertension, and myocardial infarction (MI). Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with oxidative and nitrosative stress, which can trigger the development of cardiovascular disease. Recently, emerging experimental and clinical evidence indicates that high-circulating glucose in DM is able to induce oxidative and nitrosative stress in the cardiovascular system, with the concomitant activation of an abundant nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). This process results in acute loss of the ability of the endothelium to generate nitric oxide (NO; endothelial dysfunction) and also leads to a severe functional impairment of the diabetic heart (diabetic cardiomyopathy). Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP protect against diabetic cardiovascular dysfunction. The goal of this chapter is to summarize the recently emerging evidence supporting the concept that nitrosative stress and PARP activation play a role in the pathogenesis of diabetic endothelial dysfunction and cardiovascular complications.


Endothelial Dysfunction Polymerase Activation PARP Inhibitor Diabetic Cardiomyopathy Nitrosative Stress 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Virag L, Szabo C. The therapeutic potential of poly (ADP-ribose) polymerase inhibitors. Pharmacol Rev 2002;54:375–429.PubMedCrossRefGoogle Scholar
  2. 2.
    Szabó C, Dawson VL. Role of poly (ADP-ribose) synthetase activation in inflammation and reperfusion injury. Trends Pharmacol Sci 1998;19:287–298.PubMedCrossRefGoogle Scholar
  3. 3.
    De Murcia G, Schreiber V, Molinete M, et al. Structure and function of poly(ADP-ribose) polymerase. Mol Cell Biochem 1994;138:15–24.PubMedCrossRefGoogle Scholar
  4. 4.
    Le Rhun Y, Kirkland JB, Shah GM. Cellular responses to DNA damage in the absence of Poly(ADP-ribose) polymerase. Biochem Biophys Res Commun 1998;245:1–10.PubMedCrossRefGoogle Scholar
  5. 5.
    Szabó C. Cell Death: the role of PARP. CRC Press, Boca Raton, FL: 2000.Google Scholar
  6. 6.
    De Murcia G, Shall S. (Eds.) From DNA damage and stress signaling to cell death; poly ADP-ribosylation reactions. Oxford University Press, Oxford, England, 2000.Google Scholar
  7. 7.
    Davidovic L, Vodenicharov M, Affar EB, Poirier GG. Importance of poly (ADP-ribose) glycohydrolase in the control of poly(ADP-ribose) metabolism. Exp Cell Res 2001;268:7–13.PubMedCrossRefGoogle Scholar
  8. 8.
    Rudat V, Kupper JH, Weber KJ. Trans-dominant inhibition of poly(ADP-ribosyl)ation leads to decreased recovery from ionizing radiation-induced cell killing. Int J Radiat Biol 1998;73:325–330.PubMedCrossRefGoogle Scholar
  9. 9.
    Menissier-de Murcia J, Niedergang C, Trucco C, et al. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 1997;94:7303–7307.CrossRefGoogle Scholar
  10. 10.
    Hiromatsu Y, Sato M, Yamada K, Nonaka K. Nicotinamide and 3-aminobenzamide inhibit recombinant human interferon-gamma-induced HLA-DR antigen expression, but not HLA-A, B, C antigen expression, on cultured human thyroid cells. Clin Endocrinol 1992;36:91–95.Google Scholar
  11. 11.
    Szabó C, Wong H, Bauer PI, et al. Regulation of components of the inflammatory response by 5-iodo-6-amino-1,2-benzopyrone, an inhibitor of poly (ADP-ribose) synthetase and pleiotropic modifier of cellular signal pathways. Int J Oncol 1997;10:1093–1104.Google Scholar
  12. 12.
    Ehrlich W, Huser H, Kroger H. Inhibition of the induction of collagenase by interleukin-1 beta in cultured rabbit synovial fibroblasts after treatment with the poly(ADP-ribose)-polymerase inhibitor 3-aminobenzamide. Rheumatol Int 1995;15:171–172.PubMedCrossRefGoogle Scholar
  13. 13.
    Zingarelli B, Salzman AL, Szabó C. Genetic disruption of poly (ADP ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia-reperfusion injury. Circ Res 1998;83:85–94.PubMedGoogle Scholar
  14. 14.
    Simbulan-Rosenthal CM, Ly DH, et al. Misregulation of gene expression in primary fibroblasts lacking poly(ADP-ribose) polymerase. Proc Natl Acad Sci 2000;97:11,274–11,279.PubMedCrossRefGoogle Scholar
  15. 15.
    Satoh MS, Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature 1992;356:356–358.PubMedCrossRefGoogle Scholar
  16. 16.
    Oikawa A, Tohda H, Kanai M, Miwa M, Sugimura T. Inhibitors of poly(adenosine diphosphate ribose) polymerase induce sister chromatid exchanges. Biochem Biophys Res Commun 1980;97:1311–1316.PubMedCrossRefGoogle Scholar
  17. 17.
    Park SD, Kim CG, Kim MG. Inhibitors of poly (ADP-ribose) polymerase enhance DNA strand breaks, excision repair, and sister chromatid exchanges induced by alkylating agents. Environ Mutagen 1983;5:515–525.PubMedCrossRefGoogle Scholar
  18. 18.
    Herceg Z, Wang ZQ. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 2001;477:97–110.PubMedGoogle Scholar
  19. 19.
    Poirier GG, de Murcia G, Jongstra-Bilen J, Niedergang C, Mandel P. Poly(ADP-ribosyl)ation of polynuclesomes causes relaxation of chromatin structure. Proc Natl Acad Sci 1982;79:3423–3427.PubMedCrossRefGoogle Scholar
  20. 20.
    Lautier D, Lageux J, Thibodeau J, Ménard L, Poirier GG. Molecular and biochemical features of poly (ADP-ribose) metabolism. Mol Cell Biochem 1993;122:171–193.PubMedCrossRefGoogle Scholar
  21. 21.
    Oei SL, Ziegler M. ATP for the DNA ligation step in base excision repair is generated from poly(ADP-ribose). J Biol Chem 2000;28;275:23,234–23,239.Google Scholar
  22. 22.
    Ullrich O, Ciftci O, Hass R. Proteasome activation by poly-ADP-ribose-polymerase in human myelomonocytic cells after oxidative stress. Free Radic Biol Med 2000;29:995–1004.PubMedCrossRefGoogle Scholar
  23. 23.
    Szabó C, Zingarelli B, O’Connor M, Salzman AL. DNA strand breakage, activation of poly-ADP ribosyl synthetase, and cellular energy depletion are involved in the cytotoxicity in macrophages and smooth muscle cells exposed to peroxynitrite. Proc Natl Acad Sci USA 1996;93:1753–1758.PubMedCrossRefGoogle Scholar
  24. 24.
    Szabó C, Virág L, Cuzzocrea S, et al. Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthetase. Proc Natl Acad Sci USA 1998;95:3867–3872.PubMedCrossRefGoogle Scholar
  25. 25.
    Schraufstatter IU, Hinshaw DB, Hyslop PA, Spragg RG, Cochrane CG. Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotina-mide adenine dinucleotide. J Clin Invest 1986;77:1312–1320.PubMedGoogle Scholar
  26. 26.
    Schraufstatter IU, Hyslop PA, Hinshaw DB, Spragg RG, Sklar LA, Cochrane CG. Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. Proc Natl Acad Sci USA 1986;83:4908–4912.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang J, Dawson VL, Dawson TM, Snyder SH. Nitric oxide activation of poly (ADP-ribose) synthetase in neurotoxicity. Science 1994;263:687–689.PubMedCrossRefGoogle Scholar
  28. 28.
    Radons J, Heller B, Burkle A, et al. Nitric oxide toxicity in islet cells involves poly (ADP-ribose) polymerase activation and concomitant NAD depletion. Biochem Biophys Res Comm 1994;199:1270–1277.PubMedCrossRefGoogle Scholar
  29. 29.
    Bai P, Bakondi E, Szabo EE, Gergely P, Szabo C, Virag L. Partial protection by poly(ADP-ribose) polymerase inhibitors from nitroxyl-induced cytotoxity in thymocytes. Free Radic Biol Med 2001;31:1616–1623PubMedCrossRefGoogle Scholar
  30. 30.
    Ha HC, Hester LD, Snyder SH. Poly(ADP-ribose) polymerase-1 dependence of stress-induced transcription factors and associated gene expression in glia. Proc Natl Acad Sci USA 2002;99:3270–3275.PubMedCrossRefGoogle Scholar
  31. 31.
    Hassa PO, Hottiger MO. A role of poly (ADP-ribose) polymerase in NF-kappaB transcriptional activation. Biol Chem 1999;380:953–959.PubMedCrossRefGoogle Scholar
  32. 32.
    Oliver FJ, Menissier-de Murcia J, Nacci C, et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J 1999;18:4446–4454.PubMedCrossRefGoogle Scholar
  33. 33.
    Amstad PA, Krupitza G, Cerutti PA. Mechanism of c-fos induction by active oxygen. Cancer Res 1992;52:3952–3960.PubMedGoogle Scholar
  34. 34.
    Roebuck KA, Rahman A, Lakshminarayanan V, Janakidevi K, Malik AB. H2O2 and tumor necrosis factor-alpha activate intercellular adhesion molecule 1 (ICAM-1) gene transcription through distinct cis-regulatory elements within the ICAM-1 promoter. J Biol Chem 1995;270:18,966–18,974.PubMedCrossRefGoogle Scholar
  35. 35.
    Thiemermann C, Bowes J, Myint FP, Vane JR. Inhibition of the activity of poly(ADP ribose) synthetase reduces ischemia-reperfusion injury in the heart and skeletal muscle. Proc Natl Acad Sci USA 1997;94:679–683.PubMedCrossRefGoogle Scholar
  36. 36.
    Szabo G, Bahrle S, Stumpf N, et al. Poly( ADP-Ribose) polymerase inhibition reduces reperfusion injury after heart transplantation. Circ Res 2002;90:100–106.PubMedCrossRefGoogle Scholar
  37. 37.
    Pacher P, Liaudet L, Bai P, et al. Activation of poly(ADP-ribose) polymerase contributes to the development of doxorubicin-induced heart failure. J Pharmacol Exp Ther 2002;300:862–687.PubMedCrossRefGoogle Scholar
  38. 38.
    Pacher P, Liaudet L, Mabley J, Komjati K, Szabo C. Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure. J Am Coll Cardiol 2002;40:1006–1016.PubMedCrossRefGoogle Scholar
  39. 39.
    Eliasson MJ, Sampei K, Mandir AS, et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 1997;3:1089–1095.PubMedCrossRefGoogle Scholar
  40. 40.
    Szabo C, Cuzzocrea S, Zingarelli B, O’Connor M, Salzman AL. Endothelial dysfunction in a rat model of endotoxic shock: importance of the activation of poly (ADP-ribose) synthetase by peroxynitrite. J Clin Invest 1997;100:723–735.PubMedGoogle Scholar
  41. 41.
    Soriano FG, Liaudet L, Szabo E, et al. Resistance to acute septic peritonitis in poly(ADP-ribose) polymerase-1-deficient mice. Shock. 2002;17:286–292.PubMedCrossRefGoogle Scholar
  42. 42.
    Pacher P, Cziraki A, Mabley JG, Liaudet L, Papp L, Szabo C. Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents. Biochem Pharmacol. 2002;64:1785–1791.PubMedCrossRefGoogle Scholar
  43. 43.
    Burkart V, Wang ZQ, Radons J, et al. Mice Lacking the Poly(ADP-Ribose) Polymerase Gene Are Resistant to Pancreatic Beta-Cell Destruction and Diabetes Development Induced by Streptozocin. Nat Med 1999;5:314–319.PubMedCrossRefGoogle Scholar
  44. 44.
    Pieper AA, Brat DJ, Krug DK, et al. Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci USA 1999;96:3059–3064.PubMedCrossRefGoogle Scholar
  45. 45.
    Pacher P, Mabley JG, Soriano FG, Liaudet L, Komjati K, Szabo C. Endothelial dysfunction in aging animals: the role of poly(ADP-ribose) polymerase activation. Br J Pharmacol 2002;135:1347–1350.PubMedCrossRefGoogle Scholar
  46. 46.
    Pacher P, Mabley JG, Soriano FG, Liaudet L, Szabo C. Activation of poly(ADP-ribose) polymerase contributes to the endothelial dysfunction associated with hypertension and aging. Int J Mol Med 2002;9:659–664.PubMedGoogle Scholar
  47. 47.
    Hung TH, Skepper JN, Charnock-Jones DS, Burton GJ. Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res 2002;90:1274–1281.PubMedCrossRefGoogle Scholar
  48. 48.
    Martinet W, Knaapen MW, De Meyer GR, Herman AG, Kockx MM. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation 2002;106:927–932.PubMedCrossRefGoogle Scholar
  49. 49.
    Garcia Soriano F, Virág L, Jagtap P, et al. Diabetic endothelial dysfunction: the role of poly (ADP-ribose) polymerase activation. Nature Medicine 2001;7:108–113.PubMedCrossRefGoogle Scholar
  50. 50.
    Soriano FG, Mabley JG, Pacher P, Liaudet L, Szabó C. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res 2001;89:684–691.PubMedCrossRefGoogle Scholar
  51. 51.
    Pacher P, Liaudet L, Soriano FG, Mabley JG, Szabó É, Szabó C. The role of poly (ADP-ribose) polymerase in the development of myocardial and endothelial dysfunction in diabetes mellitus. Diabetes 2002;51:514–521.PubMedCrossRefGoogle Scholar
  52. 52.
    Szabo C, Zanchi A, Komjati K, et al. Poly(ADP-Ribose) polymerase is activated in subjects at risk of developing type 2 diabetes and is associated with impaired vascular reactivity. Circulation. 2002;106:2680–2686.PubMedCrossRefGoogle Scholar
  53. 53.
    Furchgott RF. Endothelium-derived relaxing factor: discovery, early studies, and identification as nitric oxide. Biosci Rep 1999;19:235–251.PubMedCrossRefGoogle Scholar
  54. 54.
    Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000;87:840–844.PubMedGoogle Scholar
  55. 55.
    Caballero AE, Arora S, Saouaf R, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 1999;48:1856–1862.PubMedCrossRefGoogle Scholar
  56. 56.
    Ruderman NB, Williamson JR, Brownlee M. Glucose and diabetic vascular disease. FASEB J 1992;6:2905–2914.PubMedGoogle Scholar
  57. 57.
    Cosentino F, Luscher TF. Endothelial dysfunction in diabetes mellitus. J Cardiovasc Pharmacol 1998;32:S54–61.PubMedGoogle Scholar
  58. 58.
    Calles-Escandon J, Cipolla M. Diabetes and endothelial dysfunction: a clinical perspective. Endocr Rev 2001;22:36–52.PubMedCrossRefGoogle Scholar
  59. 59.
    Guzik TJ, West NE, Black E, et al. Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res 2000;86:85–90.Google Scholar
  60. 60.
    De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes. Br J Pharmacol 2000;130:963–974.PubMedCrossRefGoogle Scholar
  61. 61.
    Beckman J A. Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res 2002;90:107–111.PubMedCrossRefGoogle Scholar
  62. 62.
    Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000;404:787–790.PubMedCrossRefGoogle Scholar
  63. 63.
    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–820.PubMedCrossRefGoogle Scholar
  64. 64.
    Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996;19:257–267.PubMedCrossRefGoogle Scholar
  65. 65.
    Spitaler MM, Graier WF. Vascular targets of redox signalling in diabetes mellitus. Diabetologia. 2002;45:476–494.PubMedCrossRefGoogle Scholar
  66. 66.
    Cosentino F, Hishikawa K, Katusic ZS, Luscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 1997;96:25–28.PubMedGoogle Scholar
  67. 67.
    Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996;271:1424–1437.Google Scholar
  68. 68.
    Eiserich JP, Hristova M, Cross CE, et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998;391:393–397.PubMedCrossRefGoogle Scholar
  69. 69.
    Halliwell B. What nitrates tyrosine? Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo? FEBS Lett 1997;411:157–160.PubMedCrossRefGoogle Scholar
  70. 70.
    Ceriello A, Mercuri F, Quagliaro L, Assaloni R, Motz E, Tonutti L, Taboga C. Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress. Diabetologia. 2001;44:834–838.PubMedCrossRefGoogle Scholar
  71. 71.
    Tannous M, Rabini RA, Vignini A, et al. Evidence for iNOS-dependent peroxynitrite production in diabetic platelets. Diabetologia 1999;42:539–544.PubMedCrossRefGoogle Scholar
  72. 72.
    Pennathur S, Wagner JD, Leeuwenburgh C, Litwak KN, Heinecke JW. A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease. J Clin Invest 2001;107:853–860.PubMedGoogle Scholar
  73. 73.
    Ceriello A, Quagliaro L, Catone B, et al. Role of hyperglycemia in nitrotyrosine postprandial generation. Diabetes Care 2002;25:1439–1443.PubMedCrossRefGoogle Scholar
  74. 74.
    Frustaci A, Kajstura J, Chimenti C, et al. Myocardial cell death in human diabetes. Circ Res 2000;87:1123–1132.PubMedGoogle Scholar
  75. 75.
    Kajstura J, Fiordaliso F, Andreoli AM, et al. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 2001;50:1414–1424.PubMedCrossRefGoogle Scholar
  76. 76.
    Ceriello A, Quagliaro L, D’Amico M, et al. Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. Diabetes 2002;51:1076–1082.PubMedCrossRefGoogle Scholar
  77. 77.
    Mihm MJ, Jing L, Bauer JA. Nitrotyrosine causes selective vascular endothelial dysfunction and DNA damage. J Cardiovasc Pharmacol 2000;36:182–187.PubMedCrossRefGoogle Scholar
  78. 78.
    Zou MH, Shi C, Cohen RA. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H(2) receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes 2002;51:198–203.PubMedCrossRefGoogle Scholar
  79. 79.
    Cosentino F, Eto M, De Paolis P, et al. 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. 2003;107:1017–1023.PubMedCrossRefGoogle Scholar
  80. 80.
    Ellis EA, Guberski DL, Hutson B, Grant MB. Time course of NADH oxidase, inducible nitric oxide synthase and peroxynitrite in diabetic retinopathy in the BBZ/WOR rat. Nitric Oxide. 2002;6:295–304.PubMedCrossRefGoogle Scholar
  81. 81.
    Du Y, Smith MA, Miller CM, Kern TS. Diabetes-induced nitrative stress in the retina, and correction by aminoguanidine. J Neurochem. 2002;80:771–779.PubMedCrossRefGoogle Scholar
  82. 82.
    El-Remessy AB, Behzadian MA, Abou-Mohamed G, Franklin T, Caldwell RW, Caldwell RB. 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. 2003;162:1995–2004.PubMedGoogle Scholar
  83. 83.
    Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int 2002;61:186–194.PubMedCrossRefGoogle Scholar
  84. 84.
    Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA. Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 2001;50:1927–1937.PubMedCrossRefGoogle Scholar
  85. 85.
    Hoeldtke RD, Bryner KD, McNeill DR, et al. Nitrosative stress, uric Acid, and peripheral nerve function in early type 1 diabetes. Diabetes 2002;51:2817–2825.PubMedCrossRefGoogle Scholar
  86. 86.
    Fein FS. Diabetic cardiomyopathy. Diabetes Care 1990;13:1169–1179.PubMedCrossRefGoogle Scholar
  87. 87.
    Illan F, Valdes-Chavarri M, Tebar J, et al. Anatomical and functional cardiac abnormalities in type I diabetes. Clin Invest 1992;70:403–410.CrossRefGoogle Scholar
  88. 88.
    Joffe II, Travers KE, Perreault-Micale CL, et al. Abnormal cardiac function in the streptozotocin-induced non-insulin-dependent diabetic rat: noninvasive assessment with doppler echocardiography and contribution of the nitric oxide pathway. J Am Coll Cardiol 1999;34:2111–2119.PubMedCrossRefGoogle Scholar
  89. 89.
    Regan TJ, Ahmed S, Haider B, Moschos C, Weisse A. Diabetic cardiomyopathy: experimental and clinical observations. N Engl J Med 1994;91:776–778.Google Scholar
  90. 90.
    Bell DS. Diabetic cardiomyopathy: a unique entity or a complication of coronary artery disease? Diabetes Care 1995;18:708–714.PubMedCrossRefGoogle Scholar
  91. 91.
    Dhalla NS, Liu X, Panagia V, Takeda N. Subcellular remodeling and heart dysfunction in chronic diabetes. Cardiovasc Res 1998;40:239–247.PubMedCrossRefGoogle Scholar
  92. 92.
    Szabo C, Mabley JG, Moeller SM, et al. Soriano 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. 2002;8:571–580.PubMedGoogle Scholar
  93. 93.
    Mihm MJ, Coyle CM, Schanbacher BL, Weinstein DM, Bauer JA. Peroxynitrite induced nitration and inactivation of myofibrillar creatine kinase in experimental heart failure. Cardiovasc Res 2001;49:798–807.PubMedCrossRefGoogle Scholar
  94. 94.
    Turko IV, Marcondes S, Murad F. Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase. Am J Physiol 2001;281:2289–2294.Google Scholar
  95. 95.
    Pacher P, Liaudet L, Bai P, et al. Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation 2003;107:896–904.PubMedCrossRefGoogle Scholar
  96. 96.
    Weinstein DM, Mihm MJ, Bauer JA. Cardiac peroxynitrite formation and left ventricular dysfunction following doxorubicin treatment in mice. J Pharmacol Exp Ther 2000;294:396–401.PubMedGoogle Scholar
  97. 97.
    Mihm MJ, Bauer JA. Peroxynitrite-induced inhibition and nitration of cardiac myofibrillar creatine kinase. Biochimie 2002;84:1013–1019.PubMedCrossRefGoogle Scholar
  98. 98.
    Bianchi C, Wakiyama H, Faro R, et al. A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs. Ann Thorac Surg 2002;74:1201–1207.PubMedCrossRefGoogle Scholar
  99. 99.
    Park KS, Kim JH, Kim MS, et al. Effects of insulin and antioxidant on plasma 8-hydroxyguanine and tissue 8-hydroxydeoxyguanosine in streptozotocin-induced diabetic rats. Diabetes. 2001;50:2837–2841.PubMedCrossRefGoogle Scholar
  100. 100.
    Lorenzi M, Montisano DF, Toledo S, Wong HC. Increased single strand breaks in DNA of lymphocytes from diabetic subjects. J Clin Invest 1987;79:653–656.PubMedCrossRefGoogle Scholar
  101. 101.
    Anderson D, Yu TW, Wright J, Ioannides C. An examination of DNA strand breakage in the comet assay and antioxidant capacity in diabetic patients. Mutat Res 1998;398:151–161.PubMedGoogle Scholar
  102. 102.
    Astley S, Langrish-Smith A, Southon S, Sampson M. Vitamin E supplementation and oxidative damage to DNA and plasma LDL in type 1 diabetes. Diabetes Care 1999;22:1626–1631.PubMedCrossRefGoogle Scholar
  103. 103.
    Sardas S, Yilmaz M, Oztok U, Cakir N, Karakaya AE. Assessment of DNA strand breakage by comet assay in diabetic patients and the role of antioxidant supplementation. Mutat Res 2001;490:123–129.PubMedGoogle Scholar
  104. 104.
    Dincer Y, Akcay T, Ilkova H, Alademir Z, Ozbay G. DNA damage and antioxidant defense in peripheral leukocytes of patients with Type I diabetes mellitus. Mutat Res 2003;527:49–55.PubMedGoogle Scholar
  105. 105.
    Szabó E, Kern TS, Virag L, Mabley J, Szabó C. Evidence for poly(ADP-ribose) polymerase activation in the diabetic retina. FASEB J 2001;15:A942.Google Scholar
  106. 106.
    Wahlberg G, Carlson LA, Wasserman J, Ljungqvist A. Protective effect of nicotinamide against nephropathy in diabetic rats. Diabetes Res 1985;2:307–312.PubMedGoogle Scholar
  107. 107.
    Minchenko AG, Stevens MJ, White L, et al. Diabetes-induced overexpression of endothelin-1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP-ribose) polymerase activation. FASEB J 2003;11:1514–1516.Google Scholar
  108. 108.
    Obrosova IG, Li F, Abatan OI, et al. Role of poly(ADP-ribose) polymerase activation in diabetic neuropathy. Diabetes 2004;53(3):711–720.PubMedCrossRefGoogle Scholar
  109. 109.
    Soriano FG, Virag L, Szabo C. Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly(ADP-ribose) polymerase activation. J Mol Med 2001;79:437–448.PubMedCrossRefGoogle Scholar
  110. 110.
    Ceriello A, Piconi L, Quagliaro L, et al. Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase. J Thromb Haemost 2004;8:1453–1459.Google Scholar
  111. 111.
    Du X, Martsumura T, Edelstein D, et al. Inhibition of GAPHH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 2003;112:1049–1057.PubMedCrossRefGoogle Scholar
  112. 112.
    Komjáti K, Jagtap P, Baloglu E, VanDuzer J, Salzman AL, Szabó C. Poly(ADP-ribose) polymerase inhibition in stroke: establishment of the therapeutic window of intervention and delineation of its role in the patgogenesis of white matter damage. FASEB J 2002;16:A599.Google Scholar
  113. 113.
    Shimoda K, Murakami K, Enkhbaatar P, et al. Effect of poly(ADPribose) synthetase inhibition on burn and smoke inhalation injury in sheep. Am J Physiol Lung Cell Mol Physiol 2003;285:L240–249.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Pál Pacher
    • 1
    • 2
    • 3
  • Csaba Szabó
    • 1
    • 4
  1. 1.Inotek PharmaceuticalsBeverly
  2. 2.Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockville
  3. 3.Institute of Pharmacology and PharmacotherapySemmelweis UniversityBudapestHungary
  4. 4.Department of Human Physiology and Experimental ResearchSemmelweis UniversityBudapestHungary

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