title: Identification of cell cycle regulatory and inflammatory genes as predominant targets of p38 mitogen-activated protein kinase in the heart.
abstract: 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 p38alpha 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.
authors.affiliation: Department of Pharmacology and Toxicology, Biocenter Oulu, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Tenhunen
authors.forename: Jaana
authors.initials: J
authors.lastname: Rysä
authors.forename: Mika
authors.initials: M
authors.lastname: Ilves
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: Hanna
authors.initials: H
authors.lastname: Leskinen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D049109:Cell Proliferation; D004452:Echocardiography; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007249:Inflammation / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics; D048371:MAP Kinase Kinase 3 / Q000235:genetics; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D007527:Isoenzymes; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3