| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 2, 2002
Revised on May 22, 2003
Accepted on June 9, 2003
From the Department of Cardiology (M.T., R.B., A.T.S., D.A.G., R.J.H., J.L.M., M.S.M.), Division of Cardiovascular Science GKT, School of Medicine, KCL, The Rayne Institute, St Thomas' Hospital, London, UK; Howard Hughes Medical Institute (R.J.D.), University of Massachusetts, Worcester, Mass; and Section of Immunobiology (R.A.F.), Yale University School of Medicine, New Haven, Conn.
* To whom correspondence should be addressed. E-mail: mike.marber{at}kcl.ac.uk.
The ischemic activation of p38
mitogen-activated protein kinase (p38
-MAPK) is thought to contribute to myocardial injury. Under other circumstances, activation is through dual phosphorylation by MAPK kinase 3 (MKK3). Therefore, the mkk3-/- murine heart should be protected during ischemia. In retrogradely perfused mkk3-/- and mkk3-/- mouse hearts subjected to 30 minutes of global ischemia and 120 minutes of reperfusion, infarction/risk volume was similar (50±5 versus 51±4, P=0.93, respectively), as was intraischemic p38-MAPK phosphorylation (10 minutes ischemia as percent basal, 608±224 versus 384±104, P=0.43, respectively). This occurred despite undetectable activation of MKK3/6 in mkk3-/- hearts. However, tumor necrosis factor (TNF)-induced p38-MAPK phosphorylation was markedly diminished in mkk3-/- vs mkk3+/+ hearts (percent basal, 127±23 versus 540±267, respectively, P=0.04), suggesting an MKK-independent activation mechanism by ischemia. Hence, we examined p38-MAPK activation by TAB1-associated autophosphorylation. In wild-type mice and mkk3-/- mice, the p38-MAPK catalytic site inhibitor SB203580 (1 µmol/L) diminished phosphorylation during ischemia versus control (10 minutes ischemia as percent basal, 143±2 versus 436±96, P=0.003, and 122±25 versus 623±176, P=0.05, respectively) and reduced infarction volume (infarction/risk volume, 57±5 versus 36±3, P<0.001, and 50±5 versus 29±3, P=0.003, respectively) but did not alter TNF-induced activation, although in homogenates of ischemic hearts but not TNF-exposed hearts, p38-MAPK was associated with TAB1. Furthermore, adenovirally expressed wild-type and drug-resistant p38
-MAPK, lacking the SB203580 binding site, was phosphorylated when H9c2 myoblasts were subjected to simulated ischemia. However, SB203580 (1 µmol/L) did not prevent the phosphorylation of resistant p38
-MAPK. These findings suggest the ischemic activation of p38-MAPK contributing to myocardial injury is by TAB1-associated autophosphorylation.
This article has been cited by other articles:
![]() |
P. Sicard, S. Jacquet, K. S. Kobayashi, R. A. Flavell, and M. S. Marber Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1 Cardiovasc Res, July 15, 2009; 83(2): 277 - 284. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. E. Reichelt, L. Willems, B. A. Hack, J. N. Peart, and J. P. Headrick Cardiac and coronary function in the Langendorff-perfused mouse heart model Exp Physiol, January 1, 2009; 94(1): 54 - 70. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Y. Teos, A. Zhao, Z. Alvin, G. G. Laurence, C. Li, and G. E. Haddad Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1834 - H1845. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Nishino, I. G. Webb, S. M. Davidson, A. I. Ahmed, J. E. Clark, S. Jacquet, A. M. Shah, T. Miura, D. M. Yellon, M. Avkiran, et al. Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse Circ. Res., August 1, 2008; 103(3): 307 - 314. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Jacquet, Y. Nishino, S. Kumphune, P. Sicard, J. E. Clark, K. S. Kobayashi, R. A. Flavell, J. Eickhoff, M. Cotten, and M. S. Marber The Role of RIP2 in p38 MAPK Activation in the Stressed Heart J. Biol. Chem., May 2, 2008; 283(18): 11964 - 11971. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Makeeva, G. M. Roomans, J. W. Myers, and N. Welsh Transforming Growth Factor- -Activated Protein Kinase 1-Binding Protein (TAB)-1{alpha}, But Not TAB1 , Mediates Cytokine-Induced p38 Mitogen-Activated Protein Kinase Phosphorylation and Cell Death in Insulin-Producing Cells Endocrinology, January 1, 2008; 149(1): 302 - 309. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Jacquet, E. Zarrinpashneh, A. Chavey, A. Ginion, I. Leclerc, B. Viollet, G. A. Rutter, L. Bertrand, and M. S. Marber The relationship between p38 mitogen-activated protein kinase and AMP-activated protein kinase during myocardial ischemia Cardiovasc Res, December 1, 2007; 76(3): 465 - 472. [Abstract] [Full Text] [PDF] |
||||
![]() |
F. Y. Ma, G. H. Tesch, R. A. Flavell, R. J. Davis, and D. J. Nikolic-Paterson MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1556 - F1563. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Wang Mitogen-Activated Protein Kinases in Heart Development and Diseases Circulation, September 18, 2007; 116(12): 1413 - 1423. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. E. Clark, R. A. Flavell, M. E. Faircloth, R. J. Davis, R. J. Heads, and M. S. Marber Post-infarction remodeling is independent of mitogen-activated protein kinase kinase 3 (MKK3) Cardiovasc Res, June 1, 2007; 74(3): 466 - 470. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. I. Kim, J. H. Kwak, M. Zachariah, Y. He, L. Wang, and M. E. Choi TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1471 - F1478. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. S. Jaswal, M. Gandhi, B. A. Finegan, J. R. B. Dyck, and A. S. Clanachan p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5'-AMP-activated protein kinase Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1978 - H1985. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Fiedler, R. Feil, F. Hofmann, C. Willenbockel, H. Drexler, A. Smolenski, S. M. Lohmann, and K. C. Wollert cGMP-dependent Protein Kinase Type I Inhibits TAB1-p38 Mitogen-activated Protein Kinase Apoptosis Signaling in Cardiac Myocytes J. Biol. Chem., October 27, 2006; 281(43): 32831 - 32840. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. M. N. Kabir, J. E. Clark, M. Tanno, X. Cao, J. S. Hothersall, S. Dashnyam, D. A. Gorog, M. Bellahcene, M. J. Shattock, and M. S. Marber Cardioprotection initiated by reactive oxygen species is dependent on activation of PKC{varepsilon} Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1893 - H1899. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. J. Kang, A. Seit-Nebi, R. J. Davis, and J. Han Multiple Activation Mechanisms of p38{alpha} Mitogen-activated Protein Kinase J. Biol. Chem., September 8, 2006; 281(36): 26225 - 26234. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Bellahcene, S. Jacquet, X. B. Cao, M. Tanno, R. S. Haworth, J. Layland, A. M. Kabir, M. Gaestel, R. J. Davis, R. A. Flavell, et al. Activation of p38 Mitogen-Activated Protein Kinase Contributes to the Early Cardiodepressant Action of Tumor Necrosis Factor J. Am. Coll. Cardiol., August 1, 2006; 48(3): 545 - 555. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Zhou, M. Zheng, J. Chen, C. Xie, A. R. Kolatkar, T. Zarubin, Z. Ye, R. Akella, S. Lin, E. J. Goldsmith, et al. Determinants That Control the Specific Interactions between TAB1 and p38{alpha} Mol. Cell. Biol., May 15, 2006; 26(10): 3824 - 3834. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Lu, Y. J. Kang, J. Han, H. R. Herschman, E. Stefani, and Y. Wang TAB-1 Modulates Intracellular Localization of p38 MAP Kinase and Downstream Signaling J. Biol. Chem., March 3, 2006; 281(9): 6087 - 6095. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Okada, H. Otani, Y. Wu, S. Kyoi, C. Enoki, H. Fujiwara, T. Sumida, R. Hattori, and H. Imamura Role of F-actin organization in p38 MAP kinase-mediated apoptosis and necrosis in neonatal rat cardiomyocytes subjected to simulated ischemia and reoxygenation Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2310 - H2318. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. A. Kaiser, J. M. Lyons, J. Y. Duffy, C. J. Wagner, K. M. McLean, T. P. O'Neill, J. M. Pearl, and J. D. Molkentin Inhibition of p38 reduces myocardial infarction injury in the mouse but not pig after ischemia-reperfusion Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2747 - H2751. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Li, E. J. Miller, J. Ninomiya-Tsuji, R. R. Russell III, and L. H. Young AMP-Activated Protein Kinase Activates p38 Mitogen-Activated Protein Kinase by Increasing Recruitment of p38 MAPK to TAB1 in the Ischemic Heart Circ. Res., October 28, 2005; 97(9): 872 - 879. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Sumida, H. Otani, S. Kyoi, T. Okada, H. Fujiwara, Y. Nakao, M. Kido, and H. Imamura Temporary blockade of contractility during reperfusion elicits a cardioprotective effect of the p38 MAP kinase inhibitor SB-203580 Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2726 - H2734. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Kim, L. D. Rio, B. A. Butcher, T. H. Mogensen, S. R. Paludan, R. A. Flavell, and E. Y. Denkers p38 MAPK Autophosphorylation Drives Macrophage IL-12 Production during Intracellular Infection J. Immunol., April 1, 2005; 174(7): 4178 - 4184. [Abstract] [Full Text] [PDF] |
||||
![]() |
Q. Wang, M. Yerukhimovich, W. A. Gaarde, I. J. Popoff, and C. M. Doerschuk MKK3 and -6-dependent activation of p38{alpha} MAP kinase is required for cytoskeletal changes in pulmonary microvascular endothelial cells induced by ICAM-1 ligation Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L359 - L369. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. J. Martindale, J. A. Wall, D. M. Martinez-Longoria, P. Aryal, H. A. Rockman, Y. Guo, R. Bolli, and C. C. Glembotski Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo J. Biol. Chem., January 7, 2005; 280(1): 669 - 676. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. C Armstrong Protein kinase activation and myocardial ischemia/reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 427 - 436. [Abstract] [Full Text] [PDF] |
||||
|
Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2003 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |