Published online before print March 20, 2003, doi: 10.1161/01.RES.0000067929.01404.03
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 23, 2002
Revised on March 6, 2003
Accepted on March 11, 2003
MAP Kinase Kinase 6-p38 MAP Kinase Signaling Cascade Regulates Cyclooxygenase-2 Expression in Cardiac Myocytes In Vitro and In Vivo
Norbert Degousee ;
From the Division of Vascular Surgery (N.D., E.S., M.C., T.F.L., B.B.R.), Toronto General Hospital, Toronto, Ontario; San Diego State University Heart Institute and the Department of Biology (J.M., D.J.T., C.C.G.), San Diego State University, San Diego, Calif; and Renal Division and Department of Medicine (J.E.F., P.A.M.), St Michael's Hospital and University of Toronto, Toronto, Ontario.
* To whom correspondence should be addressed. E-mail: barry.rubin{at}uhn.on.ca.
Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in delayed prostaglandin biosynthesis. The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo. RT-PCR analysis identified p38
and p38
2 MAPK mRNA in rat cardiac myocytes. Interleukin-1 induced the phosphorylation of p38 and p382 MAPK in cardiomyocytes and stimulated RNA polymerase II binding to the COX-2 promoter, COX-2 transcription, COX-2 protein synthesis, and prostaglandin E2 (PGE2) release. Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p382 MAPK inhibited interleukin-1-induced p38 MAPK activation, COX-2 gene expression, and PGE2 release. Treatment with the p38 and p382 MAPK inhibitor, SB202190, attenuated interleukin-1-induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p382 MAPK, in the absence of interleukin-1, exhibited increased cellular p38 MAPK activity, COX-2 mRNA expression, and COX-2 protein synthesis, which was blocked by SB202190. In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates. These results provide direct evidence that MKK6 mediated p38 MAPK activation is necessary for interleukin-1-induced cardiac myocyte COX-2 gene expression and PGE2 biosynthesis in vitro and is sufficient for COX-2 gene expression by cardiac myocytes in vitro and in vivo.
Key words: MAP kinase kinase 6 • prostaglandins • recombinant proteins • transgenic mice
This article has been cited by other articles:
 |
|
 |
|
  H. Yuan, C. N. Perry, C. Huang, E. Iwai-Kanai, R. S. Carreira, C. C. Glembotski, and R. A. Gottlieb LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and is associated with cytoprotection Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H470 - H479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Kompa, F. See, D. A. Lewis, A. Adrahtas, D. M. Cantwell, B. H. Wang, and H. Krum Long-Term but Not Short-Term p38 Mitogen-Activated Protein Kinase Inhibition Improves Cardiac Function and Reduces Cardiac Remodeling Post-Myocardial Infarction J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 741 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Degousee, S. Fazel, D. Angoulvant, E. Stefanski, S.-C. Pawelzik, M. Korotkova, S. Arab, P. Liu, T. F. Lindsay, S. Zhuo, et al. Microsomal Prostaglandin E2 Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction Circulation, April 1, 2008; 117(13): 1701 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.F. Schindler, J.B. Monahan, and W.G. Smith p38 Pathway Kinases as Anti-inflammatory Drug Targets Journal of Dental Research, September 1, 2007; 86(9): 800 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Wall, J. Wei, M. Ly, P. Belmont, J. J. Martindale, D. Tran, J. Sun, W. J. Chen, W. Yu, P. Oeller, et al. Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6 Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2462 - H2472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Steer, J. M. Moran, B. S. Christmann, L. B. Maggi Jr, and J. A. Corbett Role of MAPK in the Regulation of Double-Stranded RNA- and Encephalomyocarditis Virus-Induced Cyclooxygenase-2 Expression by Macrophages. J. Immunol., September 1, 2006; 177(5): 3413 - 3420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Tenhunen, J. Rysa, M. Ilves, Y. Soini, H. Ruskoaho, and H. Leskinen Identification of Cell Cycle Regulatory and Inflammatory Genes As Predominant Targets of p38 Mitogen-Activated Protein Kinase in the Heart Circ. Res., September 1, 2006; 99(5): 485 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Degousee, D. Angoulvant, S. Fazel, E. Stefanski, S. Saha, K. Iliescu, T. F. Lindsay, J. E. Fish, P. A. Marsden, R.-K. Li, et al. c-Jun N-terminal Kinase-mediated Stabilization of Microsomal Prostaglandin E2 Synthase-1 mRNA Regulates Delayed Microsomal Prostaglandin E2 Synthase-1 Expression and Prostaglandin E2 Biosynthesis by Cardiomyocytes J. Biol. Chem., June 16, 2006; 281(24): 16443 - 16452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mitchell, A. Ota, W. Foster, B. Zhang, Z. Fang, S. Patel, S. F. Nelson, S. Horvath, and Y. Wang Distinct gene expression profiles in adult mouse heart following targeted MAP kinase activation Physiol Genomics, March 13, 2006; 25(1): 50 - 59. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. A. Chotani, S. Mitra, A. H. Eid, S. A. Han, and N. A. Flavahan Distinct cAMP signaling pathways differentially regulate {alpha}2C-adrenoceptor expression: role in serum induction in human arteriolar smooth muscle cells Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H69 - H76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. B. Robb, A. R. Carson, S. C. Tai, J. E. Fish, S. Singh, T. Yamada, S. W. Scherer, K. Nakabayashi, and P. A. Marsden Post-transcriptional Regulation of Endothelial Nitric-oxide Synthase by an Overlapping Antisense mRNA Transcript J. Biol. Chem., September 3, 2004; 279(36): 37982 - 37996. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Rebsamen, E. Perrier, C. Gerber-Wicht, J.-P. Benitah, and U. Lang Direct and Indirect Effects of Aldosterone on Cyclooxygenase-2 and Interleukin-6 Expression in Rat Cardiac Cells in Culture and after Myocardial Infarction Endocrinology, July 1, 2004; 145(7): 3135 - 3142. [Abstract] [Full Text] [PDF]
|
|