Gene Structure of a New Cardiac Peptide Hormone: A Model for Heart-Specific Gene Expression

Volume excess and mechanical load lead to the induction of the endocrine activity of the heart. The increased production and secretion of A- and B-type natriuretic peptides (ANP and BNP), in turn, unload the heart due to their physiological effects. To find out the mechanisms of cardiac-specific expression and sensitivity to mechanical stimuli of the natriuretic peptide genes, we have used salmon (Salmo salar) as our model organism, because osmoregulating fish have a particularly well developed defense mechanism against volume excess. We have previously cloned a complementary DNA from salmon heart encoding a novel vasorelaxant cardiac hormone, salmon cardiac peptide (sCP). Its production is restricted to the heart, and its release is very sensitive to mechanical load. We have now cloned the gene encoding sCP. The structure of the gene suggests that sCP may represent an ancestral form of the mammalian natriuretic peptides. Remarkably, despite the large phylogenetic distance, the sCP promoter is as effective as mammalian ANP promoters in cultured neonatal rat atrial cardiomyocytes. Therefore, structural and functional comparisons of the promoters of sCP and ANP provide an excellent means of identifying the elements and transcription factors required for atrial-specific gene expression and the regulation of the endocrine function of the heart. Isolation of the protein product of sCP gene from salmon atrium demonstrated that the storage form of sCP is the prohormone of 126 amino acids. The final processing of the prohormone appears to take place during exocytosis of the secretory granules, as the released and circulating form is the biologically active 29-amino acid sCP.