(Circulation. 1999;99:2934-2941.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Signaling Pathways in Reactive Oxygen Species–Induced Cardiomyocyte Apoptosis
From the Department of Cardiology, Franz Volhard Clinic, Humboldt-University (R.v.H., R.D.), and the Max-Delbrück-Center for Molecular Medicine (P.-F.L.), Berlin, Germany.
Correspondence to Rüdiger von Harsdorf, MD, Franz-Volhard-Klinik, Medizinische Fakultät der Charité, Humboldt-Universität, Wiltbergstr. 50, 13125 Berlin, FRG. E-mail rharsdo{at}mdc-berlin.de
Background—The importance of free radical homeostasis and apoptosis in normal and diseased hearts and their interrelationships are poorly defined. We tested whether reactive oxygen species can trigger apoptosis in cardiomyocytes, and we explored the underlying pathways.
Methods and Results—A cell culture model of isolated cardiac
cells and different reactive oxygen species (ROS)–generating systems
were used. Apoptosis became evident when
cardiomyocytes were exposed to either
H2O2 or superoxide anion
(O2-). Both H2O2- and
O2--induced apoptosis of
cardiomyocytes were associated with an increase in p53
protein content, whereas protein levels of Bax and Bcl-2 were
unaltered. H2O2, but not
O2-, induced an increase in the protein
content of Bad. Furthermore, H2O2 elicited
translocation of Bax and Bad from cytosol to mitochondria, where these
factors formed heterodimers with Bcl-2, which was followed by the
release of cytochrome c, activation of CPP32, and
cleavage of poly(ADP-ribose) polymerase. Interestingly, this pathway
was not activated by O2-. Instead,
O2- used Mch2
to promote the
apoptotic pathway, as revealed by the activation of Mch2 and
the cleavage of its substrate, lamin A.
Conclusions—Taken together, these results indicate that ROS may play an important pathophysiological role in cardiac diseases characterized by apoptotic cell death and suggest that different ROS-induced activations of the apoptotic cell death program in cardiomyocytes involve distinct signaling pathways.
Key Words: myocytes • apoptosis • reactive oxygen species • cytochrome c
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 K. C. Wollert, B. Fiedler, S. Gambaryan, A. Smolenski, J. Heineke, E. Butt, C. Trautwein, S. M. Lohmann, and H. Drexler Gene Transfer of cGMP-Dependent Protein Kinase I Enhances the Antihypertrophic Effects of Nitric Oxide in Cardiomyocytes Hypertension, January 1, 2002; 39(1): 87 - 92. [Abstract] [Full Text] [PDF]
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F. B. Mehrhof, F. U. Muller, M. W. Bergmann, P. Li, Y. Wang, W. Schmitz, R. Dietz, and R. von Harsdorf In Cardiomyocyte Hypoxia, Insulin-Like Growth Factor-I-Induced Antiapoptotic Signaling Requires Phosphatidylinositol-3-OH-Kinase-Dependent and Mitogen-Activated Protein Kinase-Dependent Activation of the Transcription Factor cAMP Response Element-Binding Protein Circulation, October 23, 2001; 104(17): 2088 - 2094. [Abstract] [Full Text] [PDF]
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F. Qin, N. K. Rounds, W. Mao, K. Kawai, and C.-s. Liang Antioxidant vitamins prevent cardiomyocyte apoptosis produced by norepinephrine infusion in ferrets Cardiovasc Res, September 1, 2001; 51(4): 736 - 748. [Abstract] [Full Text] [PDF]
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J. Kajstura, F. Fiordaliso, A. M. Andreoli, B. Li, S. Chimenti, M. S. Medow, F. Limana, B. Nadal-Ginard, A. Leri, and P. Anversa IGF-1 Overexpression Inhibits the Development of Diabetic Cardiomyopathy and Angiotensin II-Mediated Oxidative Stress Diabetes, June 1, 2001; 50(6): 1414 - 1424. [Abstract] [Full Text]
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Z. Chen, K. W. Woodburn, C. Shi, D. C. Adelman, C. Rogers, and D. I. Simon Photodynamic Therapy With Motexafin Lutetium Induces Redox-Sensitive Apoptosis of Vascular Cells Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 759 - 764. [Abstract] [Full Text] [PDF]
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G.-W. Wang, Z. Zhou, J. B. Klein, and Y. J. Kang Inhibition of hypoxia/reoxygenation-induced apoptosis in metallothionein-overexpressing cardiomyocytes Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2292 - H2299. [Abstract] [Full Text] [PDF]
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M. M. Givertz, D. B. Sawyer, and W. S. Colucci Antioxidants and Myocardial Contractility : Illuminating the "Dark Side" of {{beta}}-Adrenergic Receptor Activation? Circulation, February 13, 2001; 103(6): 782 - 783. [Full Text] [PDF]
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A. Frustaci, J. Kajstura, C. Chimenti, I. Jakoniuk, A. Leri, A. Maseri, B. Nadal-Ginard, and P. Anversa Myocardial Cell Death in Human Diabetes Circ. Res., December 8, 2000; 87(12): 1123 - 1132. [Abstract] [Full Text] [PDF]
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J. W. Adams, A. L. Pagel, C. K. Means, D. Oksenberg, R. C. Armstrong, and J. H. Brown Cardiomyocyte Apoptosis Induced by G{alpha}q Signaling Is Mediated by Permeability Transition Pore Formation and Activation of the Mitochondrial Death Pathway Circ. Res., December 8, 2000; 87(12): 1180 - 1187. [Abstract] [Full Text] [PDF]
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R. Aikawa, M. Nawano, Y. Gu, H. Katagiri, T. Asano, W. Zhu, R. Nagai, and I. Komuro Insulin Prevents Cardiomyocytes From Oxidative Stress-Induced Apoptosis Through Activation of PI3 Kinase/Akt Circulation, December 5, 2000; 102(23): 2873 - 2879. [Abstract] [Full Text] [PDF]
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V. J. Thannickal and B. L. Fanburg Reactive oxygen species in cell signaling Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1005 - L1028. [Abstract] [Full Text] [PDF]
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C. NAPOLI, O. QUEHENBERGER, F. DE NIGRIS, P. ABETE, C. K. GLASS, and W. PALINSKI Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells FASEB J, October 1, 2000; 14(13): 1996 - 2007. [Abstract] [Full Text]
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N. Hayashida, S. Chihara, E. Tayama, S. Yokose, K. Akasu, E. Kai, and S. Aoyagi Effects of angiotensin-converting enzyme inhibitor during warm blood cardioplegia Ann. Thorac. Surg., August 1, 2000; 70(2): 627 - 632. [Abstract] [Full Text] [PDF]
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F. H. Pham, P. H. Sugden, and A. Clerk Regulation of Protein Kinase B and 4E-BP1 by Oxidative Stress in Cardiac Myocytes Circ. Res., June 23, 2000; 86(12): 1252 - 1258. [Abstract] [Full Text] [PDF]
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C. Cahilly, C. M. Ballantyne, D.-S. Lim, A. Gotto, and A. J. Marian A Variant of p22phox, Involved in Generation of Reactive Oxygen Species in the Vessel Wall, Is Associated With Progression of Coronary Atherosclerosis Circ. Res., March 3, 2000; 86(4): 391 - 395. [Abstract] [Full Text] [PDF]
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A. Saraste and K. Pulkki Morphologic and biochemical hallmarks of apoptosis Cardiovasc Res, February 1, 2000; 45(3): 528 - 537. [Abstract] [Full Text] [PDF]
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C. Depre and H. Taegtmeyer Metabolic aspects of programmed cell survival and cell death in the heart Cardiovasc Res, February 1, 2000; 45(3): 538 - 548. [Abstract] [Full Text] [PDF]
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M. Rezvani, J.D. Barrans, K.-S. Dai, and C.-C. Liew Apoptosis-related genes expressed in cardiovascular development and disease: an EST approach Cardiovasc Res, February 1, 2000; 45(3): 621 - 629. [Abstract] [Full Text] [PDF]
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H. Yaoita, K. Ogawa, K. Maehara, and Y. Maruyama Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction Cardiovasc Res, February 1, 2000; 45(3): 630 - 641. [Abstract] [Full Text] [PDF]
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H. J. Oskarsson, L. Coppey, R. M. Weiss, and W.-G. Li Antioxidants attenuate myocyte apoptosis in the remote non-infarcted myocardium following large myocardial infarction Cardiovasc Res, February 1, 2000; 45(3): 679 - 687. [Abstract] [Full Text] [PDF]
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D. Ekhterae, Z. Lin, M. S. Lundberg, M. T. Crow, F. C. Brosius III, and G. Nunez ARC Inhibits Cytochrome c Release From Mitochondria and Protects Against Hypoxia-Induced Apoptosis in Heart-Derived H9c2 Cells Circ. Res., December 3, 1999; 85 (12): e70 - e77. [Abstract] [Full Text] [PDF]
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B. O’Rourke Apoptosis : Rekindling the Mitochondrial Fire Circ. Res., November 12, 1999; 85(10): 880 - 883. [Full Text] [PDF]
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S. A. Cook, P. H. Sugden, and A. Clerk Regulation of Bcl-2 Family Proteins During Development and in Response to Oxidative Stress in Cardiac Myocytes : Association With Changes in Mitochondrial Membrane Potential Circ. Res., November 12, 1999; 85(10): 940 - 949. [Abstract] [Full Text] [PDF]
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H. Kim, T.-H. Lee, E. S. Park, J. M. Suh, S. J. Park, H. K. Chung, O-Y. Kwon, Y. K. Kim, H. K. Ro, and M. Shong Role of Peroxiredoxins in Regulating Intracellular Hydrogen Peroxide and Hydrogen Peroxide-induced Apoptosis in Thyroid Cells J. Biol. Chem., June 9, 2000; 275(24): 18266 - 18270. [Abstract] [Full Text] [PDF]
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W. Wu, W.-L. Lee, Y. Y. Wu, D. Chen, T.-J. Liu, A. Jang, P. M. Sharma, and P. H. Wang Expression of Constitutively Active Phosphatidylinositol 3-Kinase Inhibits Activation of Caspase 3 and Apoptosis of Cardiac Muscle Cells J. Biol. Chem., December 15, 2000; 275(51): 40113 - 40119. [Abstract] [Full Text] [PDF]
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S. Frantz, R. A. Kelly, and T. Bourcier Role of TLR-2 in the Activation of Nuclear Factor kappa B by Oxidative Stress in Cardiac Myocytes J. Biol. Chem., February 9, 2001; 276(7): 5197 - 5203. [Abstract] [Full Text] [PDF]
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H. Han, H. Wang, H. Long, S. Nattel, and Z. Wang Oxidative Preconditioning and Apoptosis in L-cells. ROLES OF PROTEIN KINASE B AND MITOGEN-ACTIVATED PROTEIN KINASES J. Biol. Chem., July 6, 2001; 276(28): 26357 - 26364. [Abstract] [Full Text] [PDF]
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D. L. M. Hickson-Bick, G. C. Sparagna, L. M. Buja, and J. B. McMillin Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H656 - H664. [Abstract] [Full Text] [PDF]
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M. Akao, A. Ohler, B. O'Rourke, and E. Marban Mitochondrial ATP-Sensitive Potassium Channels Inhibit Apoptosis Induced by Oxidative Stress in Cardiac Cells Circ. Res., June 22, 2001; 88(12): 1267 - 1275. [Abstract] [Full Text] [PDF]
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D. R. Pimentel, J. K. Amin, L. Xiao, T. Miller, J. Viereck, J. Oliver-Krasinski, R. Baliga, J. Wang, D. A. Siwik, K. Singh, et al. Reactive Oxygen Species Mediate Amplitude-Dependent Hypertrophic and Apoptotic Responses to Mechanical Stretch in Cardiac Myocytes Circ. Res., August 31, 2001; 89(5): 453 - 460. [Abstract] [Full Text] [PDF]
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