© 1999 American Heart Association, Inc.
Cellular Biology |
The Mitochondrial Apoptotic Pathway Is Activated by Serum and Glucose Deprivation in Cardiac Myocytes
From the Departments of Medicine (Cardiology) and Cell Biology (S.B., S.M., A.L.W., R.N.K.), Albert Einstein College of Medicine, Bronx, NY; Division of Endocrinology (V.L.C., A.D.), Northwestern University Medical Center, Chicago, Ill; and Idun Pharmaceuticals (A.S.), La Jolla, Calif. S.B.'s present address is Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Correspondence to Richard N. Kitsis, Departments of Medicine (Cardiology) and Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461. E-mail kitsis{at}aecom.yu.edu
Abstract—Many cell types undergo apoptosis under conditions of ischemia. Little is known, however, about the molecular pathways that mediate this response. A cellular and biochemical approach to elucidate such signaling pathways was undertaken in primary cultures of cardiac myocytes, a cell type that is especially sensitive to ischemia-induced apoptosis. Deprivation of serum and glucose, components of ischemia in vivo, resulted in myocyte apoptosis, as determined by nuclear fragmentation, internucleosomal cleavage of DNA, and processing of caspase substrates. These manifestations of apoptosis were blocked by zVAD-fmk, a peptide caspase inhibitor, indicating that caspase activity is necessary for the progression of apoptosis in this model. In contrast to control cells, apoptotic myocytes exhibited cytoplasmic accumulation of cytochrome c, indicating release from the mitochondria. Furthermore, both caspase-9 and caspase-3 were processed to their active forms in serum-/glucose-deprived myocytes. Caspase processing, but not cytochrome c release, was inhibited by zVAD-fmk, placing the latter event upstream of caspase activation. This evidence demonstrates that components of ischemia activate the mitochondrial death pathway in cardiac myocytes.
Key Words: apoptosis • cysteine proteinase • cytochrome c • mitochondria • ischemia
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|
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|
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|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 S.-Y. Yu, S. J. Yoo, L. Yang, C. Zapata, A. Srinivasan, B. A. Hay, and N. E. Baker A pathway of signals regulating effector and initiator caspases in the developing Drosophila eye Development, January 7, 2002; 129(13): 3269 - 3278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
M. Gao, S. Fan, I. D. Goldberg, J. Laterra, R. N. Kitsis, and E. M. Rosen Hepatocyte Growth Factor/Scatter Factor Blocks the Mitochondrial Pathway of Apoptosis Signaling in Breast Cancer Cells J. Biol. Chem., December 7, 2001; 276(50): 47257 - 47265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 D. Dyntar, M. Eppenberger-Eberhardt, K. Maedler, M. Pruschy, H. M. Eppenberger, G. A. Spinas, and M. Y. Donath Glucose and Palmitic Acid Induce Degeneration of Myofibrils and Modulate Apoptosis in Rat Adult Cardiomyocytes Diabetes, September 1, 2001; 50(9): 2105 - 2113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Xu, Y. Wang, A. Ayub, and M. Ashraf Mitochondrial KATP channel activation reduces anoxic injury by restoring mitochondrial membrane potential Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1295 - H1303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Gurevich, K. M. Regula, and L. A. Kirshenbaum Serpin Protein CrmA Suppresses Hypoxia-Mediated Apoptosis of Ventricular Myocytes Circulation, April 17, 2001; 103(15): 1984 - 1991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 T. Nakagawa and J. Yuan Cross-talk between Two Cysteine Protease Families: Activation of Caspase-12 by Calpain in Apoptosis J. Cell Biol., August 21, 2000; 150(4): 887 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Kang, A. Haunstetter, H. Aoki, A. Usheva, and S. Izumo Morphological and Molecular Characterization of Adult Cardiomyocyte Apoptosis During Hypoxia and Reoxygenation Circ. Res., July 21, 2000; 87(2): 118 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Kang and S. Izumo Apoptosis and Heart Failure : A Critical Review of the Literature Circ. Res., June 9, 2000; 86(11): 1107 - 1113. [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Lin, J. M. Weinberg, R. Malhotra, S. E. Merritt, L. B. Holzman, and F. C. Brosius III GLUT-1 reduces hypoxia-induced apoptosis and JNK pathway activation Am J Physiol Endocrinol Metab, May 1, 2000; 278(5): E958 - E966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. M-Y Chi, J. Pingsterhaus, M. Carayannopoulos, and K. H. Moley Decreased Glucose Transporter Expression Triggers BAX-dependent Apoptosis in the Murine Blastocyst J. Biol. Chem., December 15, 2000; 275(51): 40252 - 40257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. I. Lee, S. Kang-Park, S.-I. Do, and Y. I. Lee The Hepatitis B Virus-X Protein Activates a Phosphatidylinositol 3-Kinase-dependent Survival Signaling Cascade J. Biol. Chem., May 11, 2001; 276(20): 16969 - 16977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Chen, H. He, S. Zhan, S. Krajewski, J. C. Reed, and R. A. Gottlieb Bid Is Cleaved by Calpain to an Active Fragment in Vitro and during Myocardial Ischemia/Reperfusion J. Biol. Chem., August 10, 2001; 276(33): 30724 - 30728. [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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