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GATA4 Mediates Activation of the B-Type Natriuretic Peptide Gene Expression in Response to Hemodynamic Stress

Departments of Pharmacology and Toxicology (M.M., N.H., M.T., H.R.) and Physiology (O.V.), Biocenter Oulu, University of Oulu, FIN-90014 University of Oulu, Finland; and Clinical Research Institute of Montreal (P.P., M.N.), University of Montréal, Montréal H2W 1R7, Canada

Address all correspondence and requests for reprints to: Heikki Ruskoaho, M.D., Ph.D., Department of Pharmacology and Toxicology, Faculty of Medicine, University of Oulu, P.O. Box 5000, FIN-90014 University of Oulu, Finland. E-mail: heikki.ruskoaho{at}oulu.fi

To identify the mechanisms that couple hemodynamic stress to alterations in cardiac gene expression, DNA constructs containing the rat B-type natriuretic peptide (BNP) promoter were injected into the myocardium of rats, which underwent bilateral nephrectomy or were sham-operated. Ventricular BNP mRNA levels were induced about 4-fold; and the BNP reporter construct containing the proximal 2200 bp, 5-fold, in response to 1-d nephrectomy. Deletion of sequences between bp -2200 and -114 did not affect basal or inducible activity of the BNP promoter. An activator protein-1-like site and two tandem GATA elements are located within this 114-bp sequence. Both deletion and mutation 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 GATA-sites abrogated the response to hemodynamic stress. The importance of these GATA elements to BNP promoter activation was further confirmed by the corresponding 38-bp oligonucleotide conferring hemodynamic stress responsiveness to a minimal BNP promoter. In gel mobility shift assays, nephrectomy increased left ventricular BNP GATA4 binding activity significantly. In conclusion, GATA elements are necessary and sufficient to confer transcriptional activation of BNP gene in response to hemodynamic stress.

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