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(Circulation. 1999;99:1685-1691.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Inhibition of p38 Mitogen-Activated Protein Kinase Decreases Cardiomyocyte Apoptosis and Improves Cardiac Function After Myocardial Ischemia and Reperfusion
From the Division of Emergency Medicine (X.L.M., F.G., B.L.L., T.A.C.), Thomas Jefferson University, Philadelphia, and the Departments of Bone and Cartilage (S.K., J.C.L.), Experimental Toxicology (C.S.L.), and Cardiovascular Pharmacology (C.W., G.Z.F., T.-L.Y.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
Correspondence to Xin L. Ma, MD, PhD, Division of Emergency Medicine, Jefferson Medical College, 1020 Sansom St, Philadelphia, PA 19107. E-mail ma1{at}jeflin.tju.edu
Background—Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in apoptotic cell death. The role of p38 MAPK in myocardial injury caused by ischemia/reperfusion, an extreme stress to the heart, is unknown.
Methods and Results—Studies were performed with isolated, Langendorff-perfused rabbit hearts. Ischemia alone caused a moderate but transient increase in p38 MAPK activity (3.5-fold increase, P<0.05 versus basal). Ischemia followed by reperfusion further activated p38 MAPK, and the maximal level of activation (6.3-fold, P<0.01) was reached 10 minutes after reperfusion. Administration of SB 203580, a p38 MAPK inhibitor, decreased myocardial apoptosis (14.7±3.2% versus 30.6±3.5% in vehicle, P<0.01) and improved postischemic cardiac function. The cardioprotective effects of SB 203580 were closely related to its inhibition of p38 MAPK. Administering SB 203580 before ischemia and during reperfusion completely inhibited p38 MAPK activation and exerted the most cardioprotective effects. In contrast, administering SB 203580 10 minutes after reperfusion (a time point when maximal MAPK activation had already been achieved) failed to convey significant cardioprotection. Moreover, inhibition of p38 MAPK attenuated myocardial necrosis after a prolonged reperfusion.
Conclusions—These results demonstrate that p38 MAPK plays a pivotal role in the signal transduction pathway mediating postischemic myocardial apoptosis and that inhibiting p38 MAPK may attenuate reperfusion injury.
Key Words: reperfusion • signal transduction • apoptosis • contractality • myocardial infarction
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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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F. Gao, T.-L. Yue, D.-W. Shi, T. A Christopher, B. L Lopez, E. H Ohlstein, F. C Barone, and X. L Ma p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation Cardiovasc Res, February 1, 2002; 53(2): 414 - 422. [Abstract] [Full Text] [PDF]
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R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
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R. M. Fryer, H. H. Patel, A. K. Hsu, and G. J. Gross Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1184 - H1192. [Abstract] [Full Text] [PDF]
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S. Sanada, M. Kitakaze, P. J. Papst, H. Asanuma, K. Node, S. Takashima, M. Asakura, H. Ogita, Y. Liao, Y. Sakata, et al. Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors: The Role of Protein Kinase A and p38 Mitogen-Activated Protein Kinase Circulation, August 7, 2001; 104(6): 705 - 710. [Abstract] [Full Text] [PDF]
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D. Tekin, L. Xi, T. Zhao, M. I. Tejero-Taldo, S. Atluri, and R. C. Kukreja Mitogen-activated protein kinases mediate heat shock-induced delayed protection in mouse heart Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H523 - H532. [Abstract] [Full Text] [PDF]
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T. A. Fischer, S. Ludwig, E. Flory, S. Gambaryan, K. Singh, P. Finn, M. A. Pfeffer, R. A. Kelly, and J. M. Pfeffer Activation of Cardiac c-Jun NH2-Terminal Kinases and p38-Mitogen-Activated Protein Kinases With Abrupt Changes in Hemodynamic Load Hypertension, May 1, 2001; 37(5): 1222 - 1228. [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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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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T. C. Zhao, D. S. Hines, and R. C. Kukreja Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial KATP channels Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1278 - H1285. [Abstract] [Full Text] [PDF]
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P. Andreka, J. Zang, C. Dougherty, T. I. Slepak, K. A. Webster, and N. H. Bishopric Cytoprotection by Jun Kinase During Nitric Oxide-Induced Cardiac Myocyte Apoptosis Circ. Res., February 16, 2001; 88(3): 305 - 312. [Abstract] [Full Text] [PDF]
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S. Sanada, M. Kitakaze, P. J. Papst, K. Hatanaka, H. Asanuma, T. Aki, Y. Shinozaki, H. Ogita, K. Node, S. Takashima, et al. Role of Phasic Dynamism of p38 Mitogen-Activated Protein Kinase Activation in Ischemic Preconditioning of the Canine Heart Circ. Res., February 2, 2001; 88(2): 175 - 180. [Abstract] [Full Text] [PDF]
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S. Schneider, W. Chen, J. Hou, C. Steenbergen, and E. Murphy Inhibition of p38 MAPK {alpha}/{beta} reduces ischemic injury and does not block protective effects of preconditioning Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H499 - H508. [Abstract] [Full Text] [PDF]
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R. K. Dubey, D. G. Gillespie, L. C. Zacharia, Z. Mi, and E. K. Jackson A2B Receptors Mediate the Antimitogenic Effects of Adenosine in Cardiac Fibroblasts Hypertension, February 1, 2001; 37(2): 716 - 721. [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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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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J. W. Mockridge, A. Punn, D. S. Latchman, M. S. Marber, and R. J. Heads PKC-dependent delayed metabolic preconditioning is independent of transient MAPK activation Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H492 - H501. [Abstract] [Full Text] [PDF]
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D. Talmor, A. Applebaum, A. Rudich, Y. Shapira, and A. Tirosh Activation of Mitogen-Activated Protein Kinases in Human Heart During Cardiopulmonary Bypass Circ. Res., May 12, 2000; 86(9): 1004 - 1007. [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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T.-L. Yue, C. Wang, J.-L. Gu, X.-L. Ma, S. Kumar, J. C. Lee, G. Z. Feuerstein, H. Thomas, B. Maleeff, and E. H. Ohlstein Inhibition of Extracellular Signal-Regulated Kinase Enhances Ischemia/Reoxygenation-Induced Apoptosis in Cultured Cardiac Myocytes and Exaggerates Reperfusion Injury in Isolated Perfused Heart Circ. Res., March 31, 2000; 86(6): 692 - 699. [Abstract] [Full Text] [PDF]
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M. A. Bogoyevitch Signalling via stress-activated mitogen-activated protein kinases in the cardiovascular system Cardiovasc Res, March 1, 2000; 45(4): 826 - 842. [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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G. Z. Feuerstein and P. R. Young Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways Cardiovasc Res, February 1, 2000; 45(3): 560 - 569. [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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S. A. Wadsworth, D. E. Cavender, S. A. Beers, P. Lalan, P. H. Schafer, E. A. Malloy, W. Wu, B. Fahmy, G. C. Olini, J. E. Davis, et al. RWJ 67657, a Potent, Orally Active Inhibitor of p38 Mitogen-Activated Protein Kinase J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 680 - 687. [Abstract] [Full Text]
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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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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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Y. Shizukuda, M. E. Reyland, and P. M. Buttrick Protein kinase C-delta modulates apoptosis induced by hyperglycemia in adult ventricular myocytes Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1625 - H1634. [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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T. C. Zhao, M. M. Taher, K. C. Valerie, and R. C. Kukreja p38 Triggers Late Preconditioning Elicited by Anisomycin in Heart: Involvement of NF-{kappa}B and iNOS Circ. Res., November 9, 2001; 89(10): 915 - 922. [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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