Pressure overload increases GATA4 binding activity via endothelin-1

Background-The signaling cascades responsible for the activation of transcr iption factors in the hypertrophic growth of cardiac myocytes during hemody namic 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 . Methods and Results-An in vivo model of intravenous administration of argin ine(8)-vasopressin (AVP) for up to 4 hours in conscious normotensive rats w as used to study the signaling mechanisms for GATA activation in response t o pressure overload. Gel mobility shift assays were used to analyze the tra ns-acting factors that interact with the GATA motifs of the BNP promoter. A VP-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 epic ardial layers of the left ventricle, whereas GATA4 and GATA6 mRNA levels re mained unchanged. Pressure overload within 15 to 60 minutes produced an inc rease in left ventricular BNP GATA4 but not GATA5 and GATA6 binding activit y, and at 30 minutes a 2.2-fold increase (P<0.001) in GATA4 binding was not ed, The mixed endothelin-1 ETA/ETB receptor antagonist bosentan but not the angiotensin II type 1 receptor antagonist losartan completely inhibited th e pressure overload-induced increase in left ventricular BNP GATA4 binding activity. Bosentan alone had no statistically significant effect on GATA4 b inding 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.