© 2000 American Heart Association, Inc.
Integrative Physiology |
Inhibition of Extracellular Signal–Regulated Kinase Enhances Ischemia/Reoxygenation–Induced Apoptosis in Cultured Cardiac Myocytes and Exaggerates Reperfusion Injury in Isolated Perfused Heart
Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-63).
From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Tian-Li Yue, Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, PO Box 1539, UW 2510, King of Prussia, PA 19406. E-mail tian-li_yue{at}sbphrd.com
Abstract—Three major mammalian mitogen-activated protein kinases, extracellular signal–regulated kinase (ERK), p38, and c-Jun NH2-terminal protein kinase (JNK), have been identified in the cardiomyocyte, but their respective roles in the heart are not well understood. The present study explored their functions and cross talk in ischemia/reoxygenation (I/R)–induced cardiac apoptosis. Exposing rat neonatal cardiomyocytes to ischemia resulted in a rapid and transient activation of ERK, p38, and JNK. On reoxygenation, further activation of all 3 mitogen-activated protein kinases was noted; peak activities increased (fold) by 5.5, 5.2, and 6.2, respectively. Visual inspection of myocytes exposed to I/R identified 18.6% of the cells as showing morphological features of apoptosis, which was further confirmed by DNA ladder and terminal deoxyribonucleotide transferase–mediated dUTP nick end labeling (TUNEL). Myocytes treated with PD98059, a MAPK/ERK kinase (MEK1/MEK2) inhibitor, displayed a suppression of I/R-induced ERK activation, whereas p38 and JNK activities were increased by 70.3% and 55.0%, respectively. In addition, the number of apoptotic cells was increased to 33.4%. With pretreatment of cells with SB242719, a selective p38 inhibitor, or SB203580, a p38 and JNK2 inhibitor, I/R+PD98059-induced apoptotic cells were reduced by 42.8% and 63.3%, respectively. Hearts isolated from rats treated with PD98059 and subjected to global ischemia (30 minutes)/reoxygenation (1 hour) showed a diminished functional recovery compared with the vehicle group. Coadministration of SB203580 attenuated the detrimental effects of PD98059 and significantly improved cardiac functional recovery. The data taken together suggest that ERK plays a protective role, whereas p38 and JNK mediate apoptosis in cardiomyocytes subjected to I/R, and the dynamic balance of their activities is critical in determining cardiomyocyte fate subsequent to reperfusional injury.
Key Words: cardiomyocyte • ischemic injury • apoptosis • mitogen-activated protein kinase
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 P. M. Becker, A. D. Verin, M. A. Booth, F. Liu, A. Birukova, and J. G. N. Garcia Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1500 - L1511. [Abstract] [Full Text] [PDF]
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S. Wei, E. C. Rothstein, L. Fliegel, L. J. Dell'Italia, and P. A. Lucchesi Differential MAP kinase activation and Na+/H+ exchanger phosphorylation by H2O2 in rat cardiac myocytes Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1542 - C1550. [Abstract] [Full Text] [PDF]
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Y. Okamoto, A. Chaves, J. Chen, R. Kelley, K. Jones, H. G. Weed, K. L. Gardner, L. Gangi, M. Yamaguchi, W. Klomkleaw, et al. Transgenic Mice with Cardiac-Specific Expression of Activating Transcription Factor 3, a Stress-Inducible Gene, Have Conduction Abnormalities and Contractile Dysfunction Am. J. Pathol., August 1, 2001; 159(2): 639 - 650. [Abstract] [Full Text]
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H. Ueda, T. Nakamura, K. Matsumoto, Y. Sawa, H. Matsuda, and T. Nakamura A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats Cardiovasc Res, July 1, 2001; 51(1): 41 - 50. [Abstract] [Full Text] [PDF]
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R. M. Fryer, P. F. Pratt, A. K. Hsu, and G. J. Gross Differential Activation of Extracellular Signal Regulated Kinase Isoforms in Preconditioning and Opioid-Induced Cardioprotection J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 642 - 649. [Abstract] [Full Text]
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E. G. Araujo, C. Bianchi, K. Sato, R. Faro, X. A. Li, and F. W. Sellke Inactivation of the MEK/ERK pathway in the myocardium during cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., April 1, 2001; 121(4): 773 - 781. [Abstract] [Full Text] [PDF]
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P. H. Wang Roads to Survival : Insulin-Like Growth Factor-1 Signaling Pathways in Cardiac Muscle Circ. Res., March 30, 2001; 88(6): 552 - 554. [Full Text] [PDF]
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K. Yamashita, J. Kajstura, D. J. Discher, B. J. Wasserlauf, N. H. Bishopric, P. Anversa, and K. A. Webster Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1 Circ. Res., March 30, 2001; 88(6): 609 - 614. [Abstract] [Full Text] [PDF]
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 A. T. SAURIN, J. L. MARTIN, R. J. HEADS, C. FOLEY, J. W. MOCKRIDGE, M. J. WRIGHT, Y. WANG, and M. S. MARBER The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes FASEB J, November 1, 2000; 14(14): 2237 - 2246. [Abstract] [Full Text]
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M. Thibonnier, D. M. Conarty, and C. L. Plesnicher Mediators of the mitogenic action of human V1 vascular vasopressin receptors Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2529 - H2539. [Abstract] [Full Text] [PDF]
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J.-i. Abe, C. P. Baines, and B. C. Berk Role of Mitogen-Activated Protein Kinases in Ischemia and Reperfusion Injury : The Good and the Bad Circ. Res., March 31, 2000; 86(6): 607 - 609. [Full Text] [PDF]
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V. L. Gabai, A. B. Meriin, J. A. Yaglom, J. Y. Wei, D. D. Mosser, and M. Y. Sherman Suppression of Stress Kinase JNK Is Involved in HSP72-mediated Protection of Myogenic Cells from Transient Energy Deprivation. HSP72 ALLEVIATES THE STRESS-INDUCED INHIBITION OF JNK DEPHOSPHORYLATION J. Biol. Chem., November 22, 2000; 275(48): 38088 - 38094. [Abstract] [Full Text] [PDF]
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T.-L. Yue, J.-L. Gu, C. Wang, A. D. Reith, J. C. Lee, R. C. Mirabile, R. Kreutz, Y. Wang, B. Maleeff, A. A. Parsons, et al. Extracellular Signal-regulated Kinase Plays an Essential Role in Hypertrophic Agonists, Endothelin-1 and Phenylephrine-induced Cardiomyocyte Hypertrophy J. Biol. Chem., November 22, 2000; 275(48): 37895 - 37901. [Abstract] [Full Text] [PDF]
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P. Liao, S.-Q. Wang, S. Wang, M. Zheng, M. Zheng, S.-J. Zhang, H. Cheng, Y. Wang, and R.-P. Xiao p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes Circ. Res., February 8, 2002; 90(2): 190 - 196. [Abstract] [Full Text] [PDF]
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V. A. Patel, Q.-J. Zhang, K. Siddle, M. A. Soos, M. Goddard, P. L. Weissberg, and M. R. Bennett Defect in Insulin-Like Growth Factor-1 Survival Mechanism in Atherosclerotic Plaque-Derived Vascular Smooth Muscle Cells Is Mediated by Reduced Surface Binding and Signaling Circ. Res., May 11, 2001; 88(9): 895 - 902. [Abstract] [Full Text] [PDF]
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F. Gao, E. Gao, T.-L. Yue, E. H. Ohlstein, B. L. Lopez, T. A. Christopher, and X.-L. Ma Nitric Oxide Mediates the Antiapoptotic Effect of Insulin in Myocardial Ischemia-Reperfusion: The Roles of PI3-Kinase, Akt, and Endothelial Nitric Oxide Synthase Phosphorylation Circulation, March 26, 2002; 105(12): 1497 - 1502. [Abstract] [Full Text] [PDF]
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