Pressure overload increases GATA4 binding activity via endothelin-1.
BACKGROUND
The signaling cascades responsible for the activation of transcription factors in the hypertrophic growth of cardiac myocytes during hemodynamic overload are largely unknown. Several of the genes upregulated in the hypertrophied heart, including B-type natriuretic peptide (BNP) gene, are controlled by the cardiac-restricted zinc finger transcription factor GATA4.


RESULTS
An in vivo model of intravenous administration of arginine(8)-vasopressin (AVP) for up to 4 hours in conscious normotensive rats was used to study the signaling mechanisms for GATA activation in response to pressure overload. Gel mobility shift assays were used to analyze the trans-acting factors that interact with the GATA motifs of the BNP promoter. AVP-induced increase in mean arterial pressure was followed by a significant increase in the BNP and c-fos mRNA levels in both the endocardial and epicardial layers of the left ventricle, whereas GATA4 and GATA6 mRNA levels remained unchanged. Pressure overload within 15 to 60 minutes produced an increase in left ventricular BNP GATA4 but not GATA5 and GATA6 binding activity, and at 30 minutes a 2.2-fold increase (P:<0.001) in GATA4 binding was noted. The mixed endothelin-1 ET(A)/ET(B) receptor antagonist bosentan but not the angiotensin II type 1 receptor antagonist losartan completely inhibited the pressure overload-induced increase in left ventricular BNP GATA4 binding activity. Bosentan alone had no statistically significant effect on GATA4 binding activity of the left ventricle in conscious animals.


CONCLUSIONS
ET-1 is a signaling molecule that rapidly upregulates GATA4 DNA binding activity in response to pressure overload in vivo.
Hautala
N
N
Departments of Pharmacology and Toxicology and Physiology, Biocenter Oulu, University of Oulu, Finland.
Tokola
H
H
Luodonpää
M
M
Puhakka
J
J
Romppanen
H
H
Vuolteenaho
O
O
Ruskoaho
H
H
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014667:Vasopressins; D016277:Ventricular Function, Left
D004268:DNA-Binding Proteins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; D014667:Vasopressins; D004247:DNA; D001120:Arginine