Document Detail


The novel chromogranin A-derived serpinin and pyroglutaminated serpinin peptides are positive cardiac β-adrenergic-like inotropes.
MedLine Citation:
PMID:  22459152     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Bruno Tota; Stefano Gentile; Teresa Pasqua; Eleonora Bassino; Hisatsugu Koshimizu; Niamh X Cawley; Maria C Cerra; Y Peng Loh; Tommaso Angelone
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2012-03-29
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  26     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-29     Completed Date:  2012-09-20     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2888-98     Citation Subset:  IM    
Affiliation:
Department of Cell Biology, University of Calabria, Arcavacata di Rende, Italy.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-1 Receptor Agonists / chemistry*,  pharmacology*
Amino Acid Sequence
Amino Acid Substitution
Animals
Cardiotonic Agents / chemistry*,  pharmacology*
Chromogranin A / chemistry*,  genetics,  pharmacology,  physiology*
Heart / drug effects*,  physiology*
Male
Molecular Sequence Data
Myocardial Contraction / drug effects
Myocardium / chemistry
Papillary Muscles / drug effects,  physiology
Peptide Fragments / chemistry*,  genetics,  pharmacology,  physiology*
Rats
Rats, Wistar
Chemical
Reg. No./Substance:
0/Adrenergic beta-1 Receptor Agonists; 0/Cardiotonic Agents; 0/Chromogranin A; 0/Peptide Fragments
Comments/Corrections

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