The novel chromogranin A‐derived serpinin and pyroglutaminated serpinin peptides are positive cardiac β‐adrenergic‐like inotropes

Three forms of serpinin peptides, serpinin (Ala26Leu), pyroglutaminated (pGlu)‐serpinin (pGlu23Leu), and serpinin‐Arg‐Arg‐Gly (Ala29Gly), are derived from cleavage at pairs of basic residues in the highly conserved C terminus of chromogranin A (CgA). Serpinin induces PN‐1 expression in neuroendocrine cells to up‐regulate granule biogenesis via a cAMP‐protein kinase A‐Sp1 pathway, while pGlu‐serpinin inhibits cell death. The aim of this study was to test the hypothesis that serpinin peptides are produced in the heart and act as novel β‐adrenergic‐like cardiac modulators. We detected serpinin peptides in the rat heart by HPLC and ELISA methods. The peptides included predominantly Ala29Gly and pGlu‐serpinin and a small amount of serpinin. Using the Langendorff perfused rat heart to evaluate the hemodynamic changes, we found that serpinin and pGlu‐serpinin exert dose‐dependent positive inotropic and lusitropic effects at 11–165 nM, within the first 5 min after administration. The pGlu‐serpinin‐induced contractility is more potent than that of serpinin, starting from 1 nM. Using the isolated rat papillary muscle preparation to measure contractility in terms of tension development and muscle length, we further corroborated the pGlu‐serpinin‐induced positive inotropism. Ala29Gly was unable to affect myocardial performance. Both pGlu‐serpinin and serpinin act through a β1‐adrenergic receptor/adenylate cyclase/cAMP/PKA pathway, indicating that, contrary to the β‐blocking profile of the other CgA‐derived cardiosuppressive peptides, vasostatin‐1 and catestatin, these two C‐terminal peptides act as β‐adrenergic‐like agonists. In cardiac tissue extracts, pGluserpinin increased intracellular cAMP levels and phosphorylation of phospholamban (PLN)Ser16, ERK1/2, and GSK‐3β. Serpinin and pGlu‐serpinin peptides emerge as novel β‐adrenergic inotropic and lusitropic modulators, suggesting that CgA and the other derived cardioactive peptides can play a key role in how the myocardium orchestrates its complex response to sympathochromaffin stimulation.—Tota, B., Gentile, S., Pasqua, T., Bassino, E., Koshimizu, H., Cawley, N. X., Cerra, M. C., Loh, Y. P., Angelone, T. The novel chromogranin A‐derived serpinin and pyroglutaminated serpinin peptides are positive cardiac β‐adrenergic‐like inotropes. FASEB J. 26, 2888–2898 (2012). www.fasebj.org