Document Detail

Obestatin affords cardioprotection to the ischemic-reperfused isolated rat heart and inhibits apoptosis in cultures of similarly stressed cardiomyocytes.
MedLine Citation:
PMID:  20525876     Owner:  NLM     Status:  MEDLINE    
Obestatin, a newly discovered peptide encoded by the ghrelin gene, induces the expression of genes regulating pancreatic beta-cell differentiation, insulin biosynthesis, and glucose metabolism. It also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase (PI3K) and ERK1/2 in pancreatic beta-cells and human islets. Since these kinases have been shown to protect against myocardial injury, we sought to investigate whether obestatin would exert cardioprotective effects. Both isolated perfused rat heart and cultured cardiomyocyte models of ischemia-reperfusion (I/R) were used to measure infarct size and cell apoptosis as end points of injury. The presence of specific obestatin receptors on cardiac cells as well as the signaling pathways underlying the obestatin effect were also studied. In the isolated heart, the addition of rat obestatin-(1-23) before ischemia reduced infarct size and contractile dysfunction in a concentration-dependent manner, whereas obestatin-(23-1), a synthetic analog with an inverse aminoacid sequence, was ineffective. The cardioprotective effect of obestatin-(1-23) was observed at concentrations of 10-50 nmol/l and was abolished by inhibiting PI3K or PKC by the addition of wortmannin (100 nmol/l) or chelerythrine, (5 micromol/l), respectively. In rat H9c2 cardiac cells or isolated ventricular myocytes subjected to I/R, 50 nmol/l obestatin-(1-23) reduced cardiomyocyte apoptosis and reduced caspase-3 activation; the antiapoptotic effect was blocked by the inhibition of PKC, PI3K, or ERK1/2 pathways. In keeping with these functional findings, radioreceptor binding results revealed the presence of specific high-affinity obestatin-binding sites, mainly localized on membranes of the ventricular myocardium and cardiomyocytes. Our data suggest that, by acting on specific receptors, obestatin-(1-23) activates PI3K, PKC-epsilon, PKC-delta, and ERK1/2 signaling and protects cardiac cells against myocardial injury and apoptosis induced by I/R.
Giuseppe Alloatti; Elisa Arnoletti; Eleonora Bassino; Claudia Penna; Maria Giulia Perrelli; Corrado Ghé; Giampiero Muccioli
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-04
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-30     Completed Date:  2010-08-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H470-81     Citation Subset:  IM    
Dipartimento di Biologia Animale e dell'Uomo, Via Accademia Albertina, 13, Torino 10123, Italy.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / antagonists & inhibitors,  metabolism
Apoptosis* / drug effects
Caspase 3 / metabolism
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors,  metabolism
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors,  metabolism
Myocardial Contraction* / drug effects
Myocardial Infarction / metabolism,  pathology,  physiopathology,  prevention & control*
Myocardial Reperfusion Injury / metabolism,  pathology,  physiopathology,  prevention & control*
Myocytes, Cardiac / drug effects,  metabolism*,  pathology
Peptide Hormones / administration & dosage,  metabolism*
Peptides / pharmacology
Protein Kinase C-delta / antagonists & inhibitors,  metabolism
Protein Kinase C-epsilon / antagonists & inhibitors,  metabolism
Protein Kinase Inhibitors / pharmacology
Receptors, Ghrelin / metabolism
Signal Transduction
Time Factors
Ventricular Function, Left* / drug effects
Reg. No./Substance:
0/Peptide Hormones; 0/Peptides; 0/Protein Kinase Inhibitors; 0/Receptors, Ghrelin; 0/obestatin, rat; EC 2.7.1.-/Prkcd protein, rat; EC 2.7.1.-/Prkce protein, rat; EC 3-Kinase; EC Kinase C-delta; EC Kinase C-epsilon; EC Protein Kinase 1; EC Protein Kinase 3; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3

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