Published online before print July 27, 2006, doi: 10.1161/01.RES.0000238387.85144.92
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 2, 2006
Revised on July 11, 2006
Accepted on July 17, 2006
Identification of Cell Cycle Regulatory and Inflammatory Genes As Predominant Targets of p38 Mitogen-Activated Protein Kinase in the Heart
Olli Tenhunen ;
From the Departments of Pharmacology and Toxicology (O.T., J.R., H.R., H.L.) and Physiology (M.I.), Biocenter Oulu; and the Department of Pathology (Y.S.), University of Oulu, Finland.
* To whom correspondence should be addressed. E-mail: heikki.ruskoaho{at}oulu.fi.
Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38
in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion, and transcription. A large number of previously unknown p38 target genes were found. Using gel mobility-shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene-expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression-induced gene expression results in myocardial cell proliferation, inflammation, and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart.
Key words: mitogen-activated protein kinases • inflammation • proliferation
Related Article:
- Inflame My Heart (by p38-MAPK)
- Angela Clerk and Peter H. Sugden
Circ. Res. 2006 99: 455-458.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  L. J. Sommerville, C. Xing, S. E. Kelemen, S. Eguchi, and M. V. Autieri Inhibition of allograft inflammatory factor-1 expression reduces development of neointimal hyperplasia and p38 kinase activity Cardiovasc Res, January 1, 2009; 81(1): 206 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Sommerville, S. E. Kelemen, and M. V. Autieri Increased Smooth Muscle Cell Activation and Neointima Formation in Response to Injury in AIF-1 Transgenic Mice Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 47 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sato, T. Horinouchi, D. S. Hutchinson, B. A. Evans, and R. J. Summers Ligand-Directed Signaling at the beta3-Adrenoceptor Produced by 3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate (SR59230A) Relative to Receptor Agonists Mol. Pharmacol., November 1, 2007; 72(5): 1359 - 1368. [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]
|
|
|
|
 |
|
 O. J. Liakopoulos, J. D. Schmitto, S. Kazmaier, A. Brauer, M. Quintel, F. A. Schoendube, and H. Dorge Cardiopulmonary and Systemic Effects of Methylprednisolone in Patients Undergoing Cardiac Surgery Ann. Thorac. Surg., July 1, 2007; 84(1): 110 - 119. [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. Crunkhorn, F. Dearie, C. Mantzoros, H. Gami, W. S. da Silva, D. Espinoza, R. Faucette, K. Barry, A. C. Bianco, and M. E. Patti Peroxisome Proliferator Activator Receptor {gamma} Coactivator-1 Expression Is Reduced in Obesity: POTENTIAL PATHOGENIC ROLE OF SATURATED FATTY ACIDS AND p38 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION J. Biol. Chem., May 25, 2007; 282(21): 15439 - 15450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Clerk and P. H. Sugden Inflame My Heart (by p38-MAPK) Circ. Res., September 1, 2006; 99(5): 455 - 458. [Full Text] [PDF]
|
|