The Chromogranin A-derived sympathomimetic serpinin depresses myocardial performance in teleost and amphibian hearts

• Serpinin peptides decrease myocardial performance in eel, goldfish and frog.
• Serpinin-elicited inotropism is mediated by a NOS/NO-dependent pathway.
• Serpinin-induced cardioinhibition involves β3-AR (goldfish) and ET-1R (frog).

Chromogranin A (CgA) is an acidic protein co-stored with catecholamines, hormones and neuropeptides in the secretory granules of endocrine, neuronal and other cell types (including cardiomyocytes). Proteolytic cleavage in the C terminus of CgA generates a 2.9 kDa peptide named serpinin (Serp; Ala26Leu) that can be modified at its N terminus to form a pyroglutamate residue (pGlu-Serp). In the rat heart, both peptides increase contractility and relaxation through a β-adrenergic-like action mechanism. Accordingly, Serp and pGlu-Serp were proposed as novel myocardial sympatho-adrenergic modulators in mammals.On a comparative basis, here we report the actions of Serp and pGlu-Serp on myocardial contractility in three poikilotherm vertebrate species: the eel (Anguilla anguilla), the goldfish (Carassius auratus) and the frog (Rana esculenta).Using isolated working heart preparations, we show that pGlu-Serp reduces stroke volume in all species tested, while Serp reduces contractility in the frog heart, but is uneffective in eel and goldfish hearts. In the goldfish and frog hearts, pGlu-Serp activates the Nitric Oxide/cGMP pathway involving Endothelin-1 B receptors (frog) and β3 adrenergic receptors (goldfish). pGlu-Serp-treated hearts from goldfish and frog show increased cGMP content. Moreover, the exposure of the frog heart to pGlu-Serp is accompanied by an increased expression of activated eNOS and Akt.In conclusion, this first report showing that pGlu-Serp inhibits mechanical cardiac performance in teleost and amphibians supports an evolutionary role of the CgA system, and particularly its serpinin component, in the sympatho-adrenergic control of the vertebrate heart.