title: The novel chromogranin A-derived serpinin and pyroglutaminated serpinin peptides are positive cardiac β-adrenergic-like inotropes.
abstract: 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, pGlu-serpinin 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.
authors.affiliation: Department of Cell Biology, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Tota
authors.forename: Stefano
authors.initials: S
authors.lastname: Gentile
authors.forename: Teresa
authors.initials: T
authors.lastname: Pasqua
authors.forename: Eleonora
authors.initials: E
authors.lastname: Bassino
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Koshimizu
authors.forename: Niamh X
authors.initials: NX
authors.lastname: Cawley
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cerra
authors.forename: Y Peng
authors.initials: YP
authors.lastname: Loh
authors.forename: Tommaso
authors.initials: T
authors.lastname: Angelone
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology*; D053379:Chromogranin A / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D002316:Cardiotonic Agents; D053379:Chromogranin A; D010446:Peptide Fragments