Abstract
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.
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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.
Francis, G.S. (2001). Diabetic cardiomyopathy: fact or fiction?. Heart 85:247–248.
Sowers, J.R., Epstein, M., and Frohlich, E.D. (2001). Diabetes, hypertension, and cardiovascular disease in update. Hypertension 37:1053–1059.
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.
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.
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.
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.
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.
McDonagh, P.F. and Hokama, J.Y. (2000). Microvascular perfusion and transport in the diabetic heart. Microcirculation 7:163–181.
Johnstone, M.T. and Veves, A. (2001). Diabetes and Cardiovascular Disease. Humana, Totowa, NJ.
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.
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.
Davies, M.J. (2000). The cardiomyopathies: an overview. Heart 83:469–474.
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.
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.
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.
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.
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.
Gustafsson, I. and Hilderbrandt, P. (2001). Editorial. Early failure of the diabetic heart. Diabetes Care 24:3–4.
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.
Chatham, J.C., Forder, J.R., and McNeill, J.H. (1996). The Heart in Diabetes. Kluwer Academic, Norwell, MA.
Guertl, B., Noehammer, C., and Hoefler, G. (2000). Metabolic cardiomyopathies. Int. J. Exp. Pathol. 81:349–372.
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.
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.
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.
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.
Rodrigues, B., Cam, M.C., and McNeill, J.H. (1998). Metabolic disturbances in diabetic cardiomyopathy. Mol. Cell. Biochem. 180:53–57.
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.
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.
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.
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.
Pogatsa, G. (2001). Metabolic energy metabolism in diabetes: therapeutic implications. Coron. Artery Dis. 12(Suppl. 1): S29-S33.
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.
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.
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.
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.
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.
Solang, L., Malmberg, K., and Ryden, L. (1999). Diabetes mellitus and congestive heart failure. Eur. Heart. J. 20: 789–795.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Kang, Y.J. (2001). Molecular and cellular mechanisms of cardiotoxicity. Environ. Health Perspect. 109(Suppl. 1): 27–34.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ohuwa, T., Sato, Y., and Naoi, M. (1995). Hydroxyl radical formation in diabetic rats induced by streptozotocin. Life Sci. 56:1789–1798.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Srinivasan, S., Stevens, M., and Wiley, J.W. (2000). Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. Diabetes 49:1932–1938.
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.
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.
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.
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Cai, L., Kang, Y.J. Oxidative stress and diabetic cardiomyopathy. Cardiovasc Toxicol 1, 181–193 (2001). https://doi.org/10.1385/CT:1:3:181
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DOI: https://doi.org/10.1385/CT:1:3:181