Mitogen-activated protein kinases p38 and ERK 1/2 mediate the wall stress-induced activation of GATA-4 binding in adult heart.
The zinc finger transcription factor GATA-4 has been implicated as a critical regulator of inducible cardiac gene expression and as a potential mediator of the hypertrophic program. However, the precise intracellular mechanisms that regulate the DNA-binding activity of GATA-4 are not fully understood. The aim of the present study was to examine the role of mitogen-activated protein kinases (p38 kinase, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase) in the left ventricular wall stress-induced activation of GATA-4 DNA binding in adult heart. Isolated perfused rat hearts were subjected to increased left ventricular wall stress by inflating a balloon in the ventricle. Gel mobility shift assays were used to analyze the transacting factors that interact with the GATA motifs of the B-type natriuretic peptide promoter. The left ventricular wall stress rapidly activated GATA-4 DNA binding and significantly increased the levels of phosphorylated p38 kinase, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase. The wall stress-induced increase in the DNA-binding activity of GATA-4 was abolished both in the presence of the p38 inhibitor SB239063 and MEK1/2 inhibitor U0126. In contrast, the inhibition of c-Jun N-terminal protein kinase by CEP11004 had no effect on the baseline or stretch-induced GATA-4 DNA binding. Moreover, GATA-4 DNA binding was up-regulated by mechanical stretch in the isolated rat atria via p38 and extracellular signal-regulated protein kinase. In conclusion, the present study demonstrates that both p38 and extracellular signal-regulated protein kinase are required for the stretch-induced GATA-4 binding in intact heart.
Tenhunen
Olli
O
Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, P. O. Box 5000, FIN-90014 University of Oulu, Finland.
Sármán
Balázs
B
Kerkelä
Risto
R
Szokodi
István
I
Papp
Lajos
L
Tóth
Miklós
M
Ruskoaho
Heikki
H
D020816:Amino Acid Motifs; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050991:GATA4 Transcription Factor; D006352:Heart Ventricles / Q000201:enzymology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D010477:Perfusion; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D002070:Butadienes; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D050991:GATA4 Transcription Factor; D009570:Nitriles; D011945:Receptors, Angiotensin; D014157:Transcription Factors; C113580:U 0126; D020097:Natriuretic Peptide, Brain; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases