Cardiovascular Toxicology

, Volume 1, Issue 3, pp 181–193 | Cite as

Oxidative stress and diabetic cardiomyopathy

A brief review
  • Lu Cai
  • Y. James KangEmail author


Diabetes is a serious public health problem. Improvements in the treatment of noncardiac complications from diabetes have resulted in heart disease becoming a leading cause of death in diabetic patients. Several cardiovascular pathological consequences of diabetes such as hypertension affect the heart to varying degrees. However, hyperglycemia, as an independent risk factor, directly causes cardiac damage and leads to diabetic cardiomyopathy. Diabetic cardiomyopathy can occur independent of vascular disease, although the mechanisms are largely unknown. Previous studies have paid little attention to the direct effects of hyperglycemia on cardiac myocytes, and most studies, especially in vitro, have mainly focused on the molecular mechanisms underlying pathogenic alterations in vascular smooth-muscle cells and endothelial cells. Thus, a comprehensive understanding of the mechanisms of diabetic cardiomyopathy is urgently needed to develop approaches for the prevention and treatment of diabetic cardiac complications. This review provides a survey of current understanding of diabetic cardiomyopathy. Current consensus is that hyperglycemia results in the production of reactive oxygen and nitrogen species, which leads to oxidative myocardial injury. Alterations in myocardial structure and function occur in the late stage of diabetes. These chronic alterations are believed to result from acute cardiac responses to suddenly increased glucose levels at the early stage of diabetes. Oxidative stress, induced by reactive oxygen and nitrogen species derived from hyperglycemia, causes abnormal gene expression, altered signal transduction, and the activation of pathways leading to programmed myocardial cell deaths. The resulting myocardial cell loss thus plays a critical role in the development of diabetic cardiomyopathy. Advances in the application of various strategies for targeting the prevention of hyperglycemia-induced oxidative myocardial injury may be fruitful.

Key Words

Cardiomyopathy diabetic complications hyperglycemia oxidative stress antioxidants 


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  1. 1.
    Grundy, S.M., Benjamin, I.J., Burke, G.L., Chait, A., Eckel, R.H., Howard, B.V., et al. (1999). Diabetes and cardiovascular disease: a statement for healthcare professionals from the American heart association. Circulation 100:1134–1146.PubMedGoogle Scholar
  2. 2.
    Francis, G.S. (2001). Diabetic cardiomyopathy: fact or fiction?. Heart 85:247–248.PubMedCrossRefGoogle Scholar
  3. 3.
    Sowers, J.R., Epstein, M., and Frohlich, E.D. (2001). Diabetes, hypertension, and cardiovascular disease in update. Hypertension 37:1053–1059.PubMedGoogle Scholar
  4. 4.
    Baynes, J.W. and Thorpe, S.R. (1999). Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Koufen, P., Ruck, A., Brdiczka, D., Wendt, S., Walliman, T., and Stark, G. (1999). Free radical-induced inactivation of creatine kinase: influence on the octameric and dimeric states of the mitochondrial enzyme (Mib-CK). Biochem. J. 344:413–417.PubMedCrossRefGoogle Scholar
  6. 6.
    Kowluru, R.A., Engerman, R.L., and Kern, T.S. (2000). Diabetes-induced metabolic abnormalities in myocardium: effect of antioxidant therapy. Free Radical Res. 32:67–74.CrossRefGoogle Scholar
  7. 7.
    Ustinova, E.E., Barrett, C.J., Sun, S.Y., and Schultz, H.D. (2000). Oxidative stress impairs cardiac chemoreflexes in diabetic rats. Am. J. Physiol. (Heart Circ. Physiol.) 279: 2176–2187.Google Scholar
  8. 8.
    Uemura, S., Matsushita, H., Li, W., Glassford, A.J., Asagami, T., Lee, K.H., et al. (2001) Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress. Circ. Res. 88:1291–1298.PubMedGoogle Scholar
  9. 9.
    McDonagh, P.F. and Hokama, J.Y. (2000). Microvascular perfusion and transport in the diabetic heart. Microcirculation 7:163–181.PubMedCrossRefGoogle Scholar
  10. 10.
    Johnstone, M.T. and Veves, A. (2001). Diabetes and Cardiovascular Disease. Humana, Totowa, NJ.Google Scholar
  11. 11.
    Rosen, P., Nawroth, P.P., King, G., Moller, W., Tritschler, H.J., and Packer, L. (2001). The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabet. Metab. Res. Rev. 17:189–212.CrossRefGoogle Scholar
  12. 12.
    Richardson, P., McKenna, W., Bristow, M., Maisch, B., Mautner, B., O’Connell, J., et al. (1996). Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task force on the definition and classification of cardiomyopathies. Circulation 93:841–842.PubMedGoogle Scholar
  13. 13.
    Davies, M.J. (2000). The cardiomyopathies: an overview. Heart 83:469–474.PubMedCrossRefGoogle Scholar
  14. 14.
    Rubler, S., Dlugash, J., Yuceoglu, Y.Z., Kumral, T., Branwood, A.W., and Grishman, A. (1972). New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am. J. Cardiol. 30:595–602.PubMedCrossRefGoogle Scholar
  15. 15.
    Stone, P.H., Muller, J.E., Hartwell, T., York, B.J., Rutherford, J.D., Parker, C.B., et al. (1989). The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. J. Am. Coll. Cardiol. 14:49–57.PubMedCrossRefGoogle Scholar
  16. 16.
    Kannel, W.B., Hjortland, M., and Castelli, W.P. (1974). Role of diabetes in congestive heart failure. The Framingham Study. Am. J. Cardiol. 34:29–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Devereux, R.B., Roman, M.J., Paranicas, M., O’Grady, M.J., Lee, E.T., Welty, T.K., et al. (2000). Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 101:2271–2276.PubMedGoogle Scholar
  18. 18.
    Van Hoeven, K.H. and Factor, S.M. (1990). A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation 82:848–855.PubMedGoogle Scholar
  19. 19.
    Gustafsson, I. and Hilderbrandt, P. (2001). Editorial. Early failure of the diabetic heart. Diabetes Care 24:3–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Roper, N.A., Bilous, R.W., Kelly, W.F., Unwin, N.C., and Connolly, V.M. (2001). Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study. Br. Med. J. 322:1389–1393.CrossRefGoogle Scholar
  21. 21.
    Chatham, J.C., Forder, J.R., and McNeill, J.H. (1996). The Heart in Diabetes. Kluwer Academic, Norwell, MA.Google Scholar
  22. 22.
    Guertl, B., Noehammer, C., and Hoefler, G. (2000). Metabolic cardiomyopathies. Int. J. Exp. Pathol. 81:349–372.PubMedCrossRefGoogle Scholar
  23. 23.
    Chatham, J.C., Gao, Z.P., and Forder, J.R. (1999). Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation. Am. J. Physiol. 277: E342-E351.PubMedGoogle Scholar
  24. 24.
    Marshall, B.A., Hansen, P.A., Ensor, N.J., Ogden, M.A., and Mueckler, M. (1999). GLUT-1 or GLUT-4 transgenes in obese mice improve glucose tolerance but do not prevent insulin resistance. Am. J. Physiol. 276:E390-E400.PubMedGoogle Scholar
  25. 25.
    Halseth, A.E., Bracy, D.P., and Wasserman, D.H. (1999). Overexpression of hexokinase II increases insulin and exercise-stimulated muscle glucose uptake in vivo. Am. J. Physiol. 276:E70-E77.PubMedGoogle Scholar
  26. 26.
    Heikkinen, S., Pietila, M., Halmekyto, M., Suppola, S., Pirinen, E., Deeb, S.S., et al. (1999). Hexokinase II-deficient mice: prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes. J. Biol. Chem. 274:22,517–22,520.CrossRefGoogle Scholar
  27. 27.
    Rodrigues, B., Cam, M.C., and McNeill, J.H. (1998). Metabolic disturbances in diabetic cardiomyopathy. Mol. Cell. Biochem. 180:53–57.PubMedCrossRefGoogle Scholar
  28. 28.
    Williamson, J.R., Chang, K., Frangos, M., Hasan, K.S., Ido, Y., Kawamura, T., et al. (1993). Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 42:801–813.PubMedCrossRefGoogle Scholar
  29. 29.
    Ramasamy, R., Oates, P.J., and Schaefer, S. (1997). Aldose reductase inhibition protects diabetic and non-diabetic rat hearts from ischemic injury. Diabetes 46:292–300.PubMedCrossRefGoogle Scholar
  30. 30.
    Trueblood, N. and Ramasamy, R. (1998). Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts. Am. J. Physiol. (Heart Circ. Physiol.) 275:75–83.Google Scholar
  31. 31.
    Nishikawa, T., Edelstein, D., Du, X.L., Yamagishi, S., Matsumura, T., Kaneda, Y., et al. (2000): Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage. Nature 404:787–790.PubMedCrossRefGoogle Scholar
  32. 32.
    Pogatsa, G. (2001). Metabolic energy metabolism in diabetes: therapeutic implications. Coron. Artery Dis. 12(Suppl. 1): S29-S33.PubMedGoogle Scholar
  33. 33.
    Knuuti, J., Takala, T.O., Nagren, K., Sipila, H., Turpeinen, A.K., Uusitupa, M.I.J., et al. (2001). Myocardial fatty acid oxidation in patients with impaired glucose tolerance. Dia-betologia 44:184–187.Google Scholar
  34. 34.
    Pawelczyk, T., Sakowicz, M., Szczepanska-Konkel, M., and Angielski, S. (2000). Decreased expression of adenosine kinase in streptozotocin-induced diabetes mellitus rats. Arch. Biochem. Biophys. 375:1–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Spindler, M., Saupe, K.W., Tian, R., Ahmed, S., Matlib, M.A., and Ingwall, J.S. (1999). Altered creatine kinase enzyme kinetics in diabetic cardiomyopathy. A 31P NMR magnetization transfer study of the intact beating rat heart. J. Mol. Cell. Cardiol. 31:2175–2189.PubMedCrossRefGoogle Scholar
  36. 36.
    Depre, C., Young, M.E., Ying, J., Ahuja, H.S., Han, Q., Garza, N., et al. (2000). Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction. J. Mol. Cell. Cardiol. 32:985–996.PubMedCrossRefGoogle Scholar
  37. 37.
    Sambandam, N., Abrahamni, M.A., Craig, S., Al-Atar, O., Jeon, E., and Rodrigues, B. (2000). Metabolism of VLDL is increased in streptozotocin-induced diabetic rat hearts. Am. J. Physiol. (Heart. Circ. Physiol.) 278:1874–1882.Google Scholar
  38. 38.
    Solang, L., Malmberg, K., and Ryden, L. (1999). Diabetes mellitus and congestive heart failure. Eur. Heart. J. 20: 789–795.PubMedCrossRefGoogle Scholar
  39. 39.
    Kawaguchi, M., Techigawara, M., Ishihata, T., Asakura, T., Saito, F., Maehara, K., et al. (1997). A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessels 12:267–274.PubMedGoogle Scholar
  40. 40.
    Tomita, M., Mukae, S., Geshi, E., Umetsu, K., Nakatani, M., and Katagiri, T. (1996). Mitochondrial respiratory impairment in streptozotocin-induced diabetic rat heart. Jpn. Circ. J. 60:673–682.PubMedCrossRefGoogle Scholar
  41. 41.
    Kuller, L.H., Velentgas, P., Barzilay, J., Beauchamp, N.J., O’Leary, D.H., and Savage, P.J. (2000). Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality. Arterioscler. Thromb. Vasc. Biol. 20:823–829.PubMedGoogle Scholar
  42. 42.
    Mathis, D.R., Liu, R.R., Rodrigues, B.B., and McNeill, J.H. (2000). Effect of hypertension on the development of diabetic cardiomyopathy. Can. J. Physiol. Pharmacol. 78: 791–798.PubMedCrossRefGoogle Scholar
  43. 43.
    Golfman, L., Dixon, I.M., Takeda, N., Lukas, A., Dakshinamurti, K., and Dhalla, N.S. (1998). Cardiac sarcolemmal Na+−Ca2+ exchange and Na+−K+ATPase activities and gene expression in alloxan-induced diabetes in rats. Mol. Cell Biochem. 188:91–101.PubMedCrossRefGoogle Scholar
  44. 44.
    Tanaka, Y., Kashiwagi, A., Saeki, Y., and Shigeta, Y. (1992). Abnormalities in cardiac alpha 1-adrenoceptor and its signal transduction in streptozocin-induced diabetic rats. Am. J. Physiol. 263:E425-E429.PubMedGoogle Scholar
  45. 45.
    Dincer, U.D., Bidasee, K.R., Guner, S., Tay, A., Ozcelikay, A.T., and Altan, V.M. (2001). The effect of diabetes on expression of beta1-, beta2-, and beta3-adrenoreceptors in rat hearts. Diabetes 50:455–461.PubMedCrossRefGoogle Scholar
  46. 46.
    Singh, J.P., Larson, M.G., O’Donnell, C.J., Wilson, P.F., Tsuji, H., Lloyd-Jones, D.M., et al. (2000). Association of hyperglycemia with reduced heart rate variability (The Framingham Heart Study). Am. J. Cardiol. 86:309–312.PubMedCrossRefGoogle Scholar
  47. 47.
    Poirier, P., Garneau, C., Marois, L., Bogaty, P., and Dumesnil, J.G. (2001). Diastolic dysfunction in normotensive men with well-controlled type-2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care 24:5–10.PubMedCrossRefGoogle Scholar
  48. 48.
    Buyukgebiz, A., Saylam, G., Dundar, B., Bober, E., Unal, N., and Akcoral, A. (2000). Dilated cardiomyopathy as the first early complication in a 14-year-old girl with diabetes mellitus type 1. J. Pediatr. Endocrinol. Metab. 13:1143–1146.PubMedGoogle Scholar
  49. 49.
    Ren, J. and Bode, M. (2000). Altered cardiac excitation-contraction coupling in ventricular myocytes from spontane-ously diabetic BB rats. Am. J. Physiol. (Heart Circ. Physiol.) 279:238–244.Google Scholar
  50. 50.
    Ren, J. and Davidoff, A.J. (1997). Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes. Am. J. Physiol. (Heart Circ. Physiol.) 272:148–158.Google Scholar
  51. 51.
    Joffe, II., Travers, K.E., Perreault-Micale, C.L., Hampton, T., Katz, S.E., Morgan, J.P., et al. (1999). 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. 34:2111–2119.PubMedCrossRefGoogle Scholar
  52. 52.
    Satoh, N., Sato, T., Shimada, M., Yamada, K., and Kitada, Y. (2001). Lusitropic effect of MCC-135 is associated with improvement of sarcoplasmic reticulum function in ventricular muscles of rats with diabetic cardiomyopathy. J. Pharmacol. Exp. Ther. 298:1161–1166.PubMedGoogle Scholar
  53. 53.
    Belke, D.D., Larsen, T.S., Gibbs, E.M., and Severson, D.L. (2000). Altered metabolism caused cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am. J. Physiol. Endocrinol. Metab. 279:1104–1113.Google Scholar
  54. 54.
    Kang, Y.J. (2001). Molecular and cellular mechanisms of cardiotoxicity. Environ. Health Perspect. 109(Suppl. 1): 27–34.PubMedCrossRefGoogle Scholar
  55. 55.
    Taniguchi, N., Kaneto, H., Asahi, M., Takahashi, M., Wenyi, C., Higashiyama, S., et al. (1996). Involvement of glycation and oxidative stress in diabetic macroangiopathy. Diabetes 45(Suppl. 3):S81-S83.PubMedGoogle Scholar
  56. 56.
    Wolff, S.P., Jiang, Z.Y., and Hunt, J.V. (1991). Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radical Biol. Med. 10:339–359.CrossRefGoogle Scholar
  57. 57.
    Mowri, H.O., Frei, B., and Keaney, J.F., Jr. (2000). Glucose enhancement of LDL oxidation is strictly metal ion dependent. Free Radical Biol. Med. 29:814–824.CrossRefGoogle Scholar
  58. 58.
    Finotti, P., Pagetta, A., and Ashton, T. (2001). The oxidative mechanism and reduces the degree of glycooxidative modifications on human serum albumin. Eur. J. Biochem. 268:2193–2200.PubMedCrossRefGoogle Scholar
  59. 59.
    Diedrich, D., Skoper, J., Diedrich, A., and Dai, F.X. (1994). Endothelial dysfunction in mesenteric resistance arteries of diabetic rats: role of free radicals. Am. J. Physiol. 266:H1153-H1161.Google Scholar
  60. 60.
    Giardino, I., Fard, A.K., Hatchell, D.L., and Brownlee, M. (1998). Aminiguanidine inhibits reactive oxygen species formation, lipid peroxidation, and oxidant-induced apoptosis. Diabetes 47:1114–1120.PubMedCrossRefGoogle Scholar
  61. 61.
    Rosen, P., Du, X., and Tschope, D. (1998). Role of oxygen derived radicals for vascular dysfunction in the diabetic heart: prevention by alpha-tocopherol? Mol. Cell. Biochem. 188:103–111.PubMedCrossRefGoogle Scholar
  62. 62.
    Du, X.L., Stockklauser-Farber, K., and Rosen, P. (1999). Generation of reactive oxygen intermediates, activation of NFkappaB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radical Med. Biol. 27:752–763.CrossRefGoogle Scholar
  63. 63.
    Ha, H. and Lee, H.B. (2000). Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucose. Kidney Int. 58(Suppl. 77):S19-S25.CrossRefGoogle Scholar
  64. 64.
    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.PubMedGoogle Scholar
  65. 65.
    Inoguchi, T., Li, P., Umeda, F., Yu, H.Y., Kakimoto, M., Imamura, M., Aoki, T., et al. (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.PubMedCrossRefGoogle Scholar
  66. 66.
    Peiro, C., Lafuente, N., Matesanz, N., Cercas, E., Llergo, J.L., Vallejo, S., et al. (2001). High glucose induced cell death of cultured human aortic smooth muscle cells through the formation of hydrogen peroxide. Br. J. Pharmacol. 133: 967–974.PubMedCrossRefGoogle Scholar
  67. 67.
    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. 269:788–791.Google Scholar
  68. 68.
    Yeh, C.H., Sturgis, L., Haidacher, J., Zhang, X.N., Sherwood, S.J., Bjercke, R.J., et al. (2001). Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 50:1495–1504.PubMedCrossRefGoogle Scholar
  69. 69.
    Kakkar, R., Kalra, J., Mantha, S.V., and Prasad, K. (1995). Lipid peroxidation and activity of antioxidant enzymes in diabetic rats. Mol. Cell. Biochem. 151:113–119.PubMedCrossRefGoogle Scholar
  70. 70.
    Ohuwa, T., Sato, Y., and Naoi, M. (1995). Hydroxyl radical formation in diabetic rats induced by streptozotocin. Life Sci. 56:1789–1798.CrossRefGoogle Scholar
  71. 71.
    Pennathur, S., Wagner, J.D., Leeuwenbergh, C., Litwak, K.N., and Heinecke, J.W. (2001). A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease. J. Clin. Invest. 107:853–860.PubMedGoogle Scholar
  72. 72.
    Kajstura, J., Fiordaliso, F., Andreoli, A.M., Li, B., Chimenti, S., Marvin, S., et al. (2001). IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 50:1414–1424.PubMedCrossRefGoogle Scholar
  73. 73.
    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.PubMedGoogle Scholar
  74. 74.
    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.PubMedGoogle Scholar
  75. 75.
    Kucharska, J., Braunova, Z., Ulicna, O., Zlatos, L., and Gvozdjakova, A. (2000). Deficit of coenzyme Q in heart and liver mitochondria of rats with streptozotocin-induced diabetes. Physiol. Res. 49:411–418.PubMedGoogle Scholar
  76. 76.
    Hayashi, H., Iimuro, M., Matsumoto, Y., and Kaneko, M. (1998). Effects of gamma-glutamylcysteine ethyl ester on heart mitochondrial creatine kinase activity: involvement of sulfhydryl groups. Eur. J. Pharmacol. 349:133–136.PubMedCrossRefGoogle Scholar
  77. 77.
    Kaneko, M., Matsumoto, Y., Hayashi, H., Kobayashi, A., and Yamazaki, N. (1994). Oxygen free radicals and calcium homeostasis in the heart. Mol. Cell. Biochem. 139:91–100.PubMedCrossRefGoogle Scholar
  78. 78.
    Matsui, H., Okumura, K., Mukawa, H., Hibino, M., Toki, Y., and Ito, T. (1997). Increased oxysterol contents in diabetic rat hearts: their involvement in diabetic cardiomyopathy. Can. J. Cardiol. 13:373–379.PubMedGoogle Scholar
  79. 79.
    Siwik, D., Pagano, P.J., and Colucci, W.S. (2001). Oxidative stress regulates collagen synthesis and matrix metallo-proteinase activity in cardiac fibroblasts. Am. J. Physiol. Cell Physiol. 280:C53-C60.PubMedGoogle Scholar
  80. 80.
    Monnier, V.M., Glomb, M., Elgawish, A., and Sell, D.R. (1996). The mechanism of collagen cross-linking in diabetes: A puzzle nearing resolution. Diabetes 45:S67-S72.PubMedCrossRefGoogle Scholar
  81. 81.
    Yamagishi, S., Edelstein, D., Du, X.-L., and Brownlee, M. (2001). Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. Diabetes 50:1491–1494.PubMedCrossRefGoogle Scholar
  82. 82.
    Doroshow, J.H., Locker, G.Y., and Myers, C.E. (1980). Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J. Clin. Invest. 65:128–135.PubMedCrossRefGoogle Scholar
  83. 83.
    Chen, Y., Saari, J.T., and Kang, Y.J. (1994). Weak antioxidant defenses make the heart a target for damage in copper-deficient rats. Free Radical Biol. Med. 17:529–536.CrossRefGoogle Scholar
  84. 84.
    Kersten, J.R., Schmeling, T.J., Orth, K.G., Pagel, P.S., and Warltier, D.C. (1998). Acute hyperglycemia abolishes ischemic preconditioning in vivo. Am. J. Physiol. 275:H721-H725.PubMedGoogle Scholar
  85. 85.
    Joyeux, M., Faure, P., Godin-Ribuot, D., Halimi, S., Patel, A., Yellon, D.M., et al. (1999). Heat stress fails to protect myocardium of streptozotocin-induced diabetic rats against infarction. Cardiovasc. Res. 43:939–946.PubMedCrossRefGoogle Scholar
  86. 86.
    Elangovan, V., Shohami, E., Gati, I., and Kohen, R. (2000). Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocin-induced diabetic rats: a cyclic voltametry study. Free Radical Res. 32:125–134.CrossRefGoogle Scholar
  87. 87.
    Alici, B., Gumustas, M.K., Ozkara, H., Akkus, E., Demirel, G., Yencilek, F., et al. (2000). Apoptosis in the erectile tissues of diabetic and healthy rats. BJU International 85:326–329.PubMedCrossRefGoogle Scholar
  88. 88.
    Cai, L., Chen, S., Evans, T., Deng, D.X., Mukherjee, K., and Chakrabarti, S. (2000). Apoptotic germ-cell death and testicular damage in experimental diabetes: prevention by endothelin antagonism. Urol. Res. 28:342–347.PubMedCrossRefGoogle Scholar
  89. 89.
    Srinivasan, S., Stevens, M., and Wiley, J.W. (2000). Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. Diabetes 49:1932–1938.PubMedCrossRefGoogle Scholar
  90. 90.
    Fiordaliso, F., Li, B., Latini, R., Sonnenblick, E.H., Anversa, P., Leri, A., et al. (2000). Myocyte death in streptozotocin-induced diabetes in rats is angiotensin II-dependent. Lab. Invest. 80:531–527.Google Scholar
  91. 91.
    Listenberger, L.L., Ory, D.S., and Schaffer, J.E. (2001). Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J. Biol. Chem. 276:14,890–14,895.CrossRefGoogle Scholar
  92. 92.
    Chi, M.M., Pingsterhause, J., Carayannopoulos, M., and Moley, K.H. (2000). Decreased glucose transporter expression triggers BAX-dependent apoptosis in the murine blastocyst. J. Biol. Chem. 275:40,252–40,257.Google Scholar

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© Humana Press Inc 2001

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisville
  2. 2.Jewish Hospital Heart and Lung InstituteLouisville
  3. 3.Department of MedicineUniversity of Louisville School of MedicineLouisville

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