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 ac tivity of the heart. The increased production and secretion of A- and B-typ e natriuretic peptides (ANP and BNP), in turn, unload the heart due to thei r physiological effects. To find out the mechanisms of cardiac-specific exp ression and sensitivity to mechanical stimuli of the natriuretic peptide ge nes, we have used salmon (Salmo salar) as our model organism, because osmor egulating fish have a particularly well developed defense mechanism against volume excess. We have previously cloned a complementary DNA from salmon h eart encoding a novel vasorelaxant cardiac hormone, salmon cardiac peptide (sCP). Its production is restricted to the heart, and its release is very s ensitive 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 phylogene tic distance, the sCP pro meter is as effective as mammalian ANP promoters in cultured neonatal rat atrial cardiomyocytes. Therefore, structural and f unctional comparisons of the promoters of sCP and ANP provide an excellent means of identifying the elements and transcription factors required for at rial-specific gene expression and the regulation of the endocrine function of the heart. Isolation of the protein product of sCP gene from salmon atri um 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.