title: Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms.
abstract: Persistent controversy underlies the functional roles of specific p38 MAPK isoforms in cardiac biology and regulation of hypertrophy-associated genes. Here we show that adenoviral gene transfer of p38β but not p38α increased B-type natriuretic peptide (BNP) mRNA levels in vitro as well as atrial natriuretic peptide mRNA levels both in vitro and in vivo. Overexpression of p38α, in turn, augmented the expression fibrosis-related genes connective tissue growth factor, basic fibroblast growth factor and matrix metalloproteinase-9 both in vitro and in vivo. p38β-induced BNP transcription was diminished by mutation of GATA-4 binding site, whereas overexpression of MKK6b, an upstream regulator of p38α and p38β, activated BNP transcription through both GATA-4 and AP-1. Overexpression of MKK3, upstream regulator of p38α, induced BNP transcription independently from AP-1 and GATA-4. These data provide new evidence for diversity in downstream targets and functional roles of p38 pathway kinases in regulation of hypertrophy-associated cardiac genes.
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Koivisto
authors.forename: Leena
authors.initials: L
authors.lastname: Kaikkonen
authors.forename: Heikki
authors.initials: H
authors.lastname: Tokola
authors.forename: Sampsa
authors.initials: S
authors.lastname: Pikkarainen
authors.forename: Jani
authors.initials: J
authors.lastname: Aro
authors.forename: Harri
authors.initials: H
authors.lastname: Pennanen
authors.forename: Teemu
authors.initials: T
authors.lastname: Karvonen
authors.forename: Jaana
authors.initials: J
authors.lastname: Rysä
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C526316:CCN2 protein, rat; D050991:GATA4 Transcription Factor; D007093:Imidazoles; D007527:Isoenzymes; D011725:Pyridines; D016222:Fibroblast Growth Factor 2; D020097:Natriuretic Peptide, Brain; D055513:Connective Tissue Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020780:Matrix Metalloproteinase 9; C093642:SB 203580