GATA4 mediates activation of the B-type natriuretic peptide gene expression in response to hemodynamic stress

To identify the mechanisms that couple hemodynamic stress to alterations in cardiac gene expression, DNA constructs containing the rat B-type natriure tic peptide (BNP) promoter were injected into the myocardium of rats, which underwent bilateral nephrectomy or were sham-operated. Ventricular BNP mRN A levels were induced about 4-fold; and the BNP reporter construct containi ng the proximal 2200 bp, 5-fold, in response to 1-d nephrectomy. Deletion o f sequences between bp -2200 and -114 did not affect basal or inducible act ivity of the BNP promoter. An activator protein-l-like site and two tandem GATA elements are located within this 114-bp sequence. Both deletion and mu tation of the AP-1-like motif decreased basal activity but did not abolish the response to nephrectomy. In contrast, mutation or deletion of -90 bp GA TA-sites abrogated the response to hemodynamic stress. The importance of th ese GATA elements to BNP promoter activation was further confirmed by the c orresponding 38-bp oligonucleotide conferring hemodynamic stress responsive ness to a minimal BNP promoter. In gel mobility shift assays, nephrectomy i ncreased left ventricular BNP GATA4 binding activity significantly. In conc lusion, GATA elements are necessary and sufficient to confer transcriptiona l activation of BNP gene in response to hemodynamic stress.