© 2000 American Heart Association, Inc.
Clinical Research |
Myocardial Cell Death in Human Diabetes
From the Department of Medicine (J.K., I.J., A.L., B.N.-G., P.A.), New York Medical College, Valhalla, NY, and Department of Cardiology (A.F., C.C., A.M.), Sacred Heart University, Rome, Italy.
Correspondence to Piero Anversa, MD, Department of Medicine, New York Medical College, Vosburgh Pavilion, Room 302, Valhalla, NY 10595. E-mail piero_anversa{at}nymc.edu
Abstract—The renin-angiotensin system is upregulated with diabetes, and this may contribute to the development of a dilated myopathy. Angiotensin II (Ang II) locally may lead to oxidative damage, activating cardiac cell death. Moreover, diabetes and hypertension could synergistically impair myocardial structure and function. Therefore, apoptosis and necrosis were measured in ventricular myocardial biopsies obtained from diabetic and diabetic-hypertensive patients. Accumulation of a marker of oxidative stress, nitrotyrosine, and Ang II labeling were evaluated quantitatively. The diabetic heart showed cardiac hypertrophy, cavitary dilation, and depressed ventricular performance. These alterations were more severe with diabetes and hypertension. Diabetes was characterized by an 85-fold, 61-fold, and 26-fold increase in apoptosis of myocytes, endothelial cells, and fibroblasts, respectively. Apoptosis in cardiac cells did not increase additionally with diabetes and hypertension. Diabetes increased necrosis by 4-fold in myocytes, 9-fold in endothelial cells, and 6-fold in fibroblasts. However, diabetes and hypertension increased necrosis by 7-fold in myocytes and 18-fold in endothelial cells. Similarly, Ang II labeling in myocytes and endothelial cells increased more with diabetes and hypertension than with diabetes alone. Nitrotyrosine localization in cardiac cells followed a comparable pattern. In spite of the difference in the number of nitrotyrosine-positive cells with diabetes and with diabetes and hypertension, apoptosis and necrosis of myocytes, endothelial cells, and fibroblasts were detected only in cells containing this modified amino acid. In conclusion, local increases in Ang II with diabetes and with diabetes and hypertension may enhance oxidative damage, activating cardiac cell apoptosis and necrosis.
Key Words: oxidative damage • renin-angiotensin system • nitrotyrosine • heart failure
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 M. Nishimura, T. Hashimoto, H. Kobayashi, T. Fukuda, K. Okino, N. Yamamoto, N. Nakamura, T. Yoshikawa, H. Takahashi, and T. Ono Association between cardiovascular autonomic neuropathy and left ventricular hypertrophy in diabetic haemodialysis patients Nephrol. Dial. Transplant., October 1, 2004; 19(10): 2532 - 2538. [Abstract] [Full Text] [PDF]
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 H. S. Lim, R. J. MacFadyen, and G. Y. H. Lip Diabetes Mellitus, the Renin-Angiotensin-Aldosterone System, and the Heart Arch Intern Med, September 13, 2004; 164(16): 1737 - 1748. [Abstract] [Full Text] [PDF]
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 Z. Y. Fang, J. B. Prins, and T. H. Marwick Diabetic Cardiomyopathy: Evidence, Mechanisms, and Therapeutic Implications Endocr. Rev., August 1, 2004; 25(4): 543 - 567. [Abstract] [Full Text] [PDF]
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L. Raimondi, P. De Paoli, E. Mannucci, G. Lonardo, L. Sartiani, G. Banchelli, R. Pirisino, A. Mugelli, and E. Cerbai Restoration of Cardiomyocyte Functional Properties by Angiotensin II Receptor Blockade in Diabetic Rats Diabetes, July 1, 2004; 53(7): 1927 - 1933. [Abstract] [Full Text] [PDF]
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Y. Shimoni and X.-F. Liu Gender differences in ANG II levels and action on multiple K+ current modulation pathways in diabetic rats Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H311 - H319. [Abstract] [Full Text] [PDF]
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J. I. Barzilay, R. A. Kronmal, J. S. Gottdiener, N. L. Smith, G. L. Burke, R. Tracy, P. J. Savage, and M. Carlson The association of fasting glucose levels with congestive heart failure in diabetic adults >=65 years: The Cardiovascular Health Study J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2236 - 2241. [Abstract] [Full Text] [PDF]
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 K. Doi, K. Hasegawa, M. Fujita, A. Yamazato, K. Yamanaka, M. Watanabe, K. Tambara, and M. Komeda Clinical characteristics relevant to myocardial cell apoptosis: analysis of pericardial fluid Interactive CardioVascular and Thoracic Surgery, June 1, 2004; 3(2): 359 - 362. [Abstract] [Full Text] [PDF]
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R. Liu, T. Desta, H. He, and D. T. Graves Diabetes Alters the Response to Bacteria by Enhancing Fibroblast Apoptosis Endocrinology, June 1, 2004; 145(6): 2997 - 3003. [Abstract] [Full Text] [PDF]
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Y. Pang, P. Bounelis, J. C. Chatham, and R. B. Marchase Hexosamine Pathway Is Responsible for Inhibition by Diabetes of Phenylephrine-Induced Inotropy Diabetes, April 1, 2004; 53(4): 1074 - 1081. [Abstract] [Full Text] [PDF]
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D. Torella, M. Rota, D. Nurzynska, E. Musso, A. Monsen, I. Shiraishi, E. Zias, K. Walsh, A. Rosenzweig, M. A. Sussman, et al. Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 Overexpression Circ. Res., March 5, 2004; 94(4): 514 - 524. [Abstract] [Full Text] [PDF]
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Y. Shimoni, M. Chuang, E. D. Abel, and David. L. Severson Gender-dependent attenuation of cardiac potassium currents in type 2 diabetic db/db mice J. Physiol., March 1, 2004; 555(2): 345 - 354. [Abstract] [Full Text] [PDF]
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R. Marfella, C. Di Filippo, K. Esposito, F. Nappo, E. Piegari, S. Cuzzocrea, L. Berrino, F. Rossi, D. Giugliano, and M. D'Amico Absence of Inducible Nitric Oxide Synthase Reduces Myocardial Damage During Ischemia Reperfusion in Streptozotocin-Induced Hyperglycemic Mice Diabetes, February 1, 2004; 53(2): 454 - 462. [Abstract] [Full Text]
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Y. Chandrashekhar, S. Sen, R. Anway, A. Shuros, and I. Anand Long-Term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction J. Am. Coll. Cardiol., January 21, 2004; 43(2): 295 - 301. [Abstract] [Full Text] [PDF]
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L. Quagliaro, L. Piconi, R. Assaloni, L. Martinelli, E. Motz, and A. Ceriello 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, November 1, 2003; 52(11): 2795 - 2804. [Abstract] [Full Text] [PDF]
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C.-H. Huang, S. F. Vatner, A. P. Peppas, G. Yang, and R. K. Kudej Cardiac Nerves Affect Myocardial Stunning Through Reactive Oxygen and Nitric Oxide Mechanisms Circ. Res., October 31, 2003; 93(9): 866 - 873. [Abstract] [Full Text] [PDF]
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 T Hayashi, K Sohmiya, A Ukimura, S Endoh, T Mori, H Shimomura, M Okabe, F Terasaki, and Y Kitaura Angiotensin II receptor blockade prevents microangiopathy and preserves diastolic function in the diabetic rat heart Heart, October 1, 2003; 89(10): 1236 - 1242. [Abstract] [Full Text] [PDF]
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C. Cheng and D. W. Zochodne Sensory Neurons With Activated Caspase-3 Survive Long-Term Experimental Diabetes Diabetes, September 1, 2003; 52(9): 2363 - 2371. [Abstract] [Full Text] [PDF]
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A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez Cardiomyocyte apoptosis in hypertensive cardiomyopathy Cardiovasc Res, September 1, 2003; 59(3): 549 - 562. [Abstract] [Full Text] [PDF]
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E. Picano Diabetic cardiomyopathy: the importance of being earliest J. Am. Coll. Cardiol., August 6, 2003; 42(3): 454 - 457. [Full Text] [PDF]
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 A. Ceriello New Insights on Oxidative Stress and Diabetic Complications May Lead to a "Causal" Antioxidant Therapy Diabetes Care, May 1, 2003; 26(5): 1589 - 1596. [Abstract] [Full Text] [PDF]
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M. A. Fortuno, A. Gonzalez, S. Ravassa, B. Lopez, and J. Diez Clinical implications of apoptosis in hypertensive heart disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1495 - H1506. [Full Text] [PDF]
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A. S. Neitzel, A. N. Carley, and D. L. Severson Chylomicron and palmitate metabolism by perfused hearts from diabetic mice Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E357 - E365. [Abstract] [Full Text] [PDF]
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 I. V. Turko and F. Murad Protein Nitration in Cardiovascular Diseases Pharmacol. Rev., December 1, 2002; 54(4): 619 - 634. [Abstract] [Full Text] [PDF]
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