title: Urocortin-1 Mediated Cardioprotection Involves XIAP and CD40-Ligand Recovery: Role of EPAC2 and ERK1/2.
abstract: OBJECTIVE
  Urocortin-1 (Ucn-1) is an endogenous peptide that protects heart from ischemia and reperfusion (I/R) injuries. Ucn-1 is known to prevent cardiac cell death, but its role in the transcription of specific genes related to survival signaling pathway has not been fully defined. The aim of this study was to investigate the molecular signaling implicated in the improvement of cardiac myocytes survival induced by Ucn-1.
  
  
  RESULTS
  Ucn-1 administration before ischemia and at the onset of reperfusion, in rat hearts perfused in Langendorff system, fully recovered heart contractility and other hemodynamic parameters. Ucn-1 enhanced cell viability and decreased lactate dehydrogenase (LDH) release in adult cardiac myocytes subjected to simulated I/R. Annexin V-FITC/PI staining indicated that Ucn-1 promoted cell survival and decreased cell necrosis through Epac2 (exchange protein directly activated by cAMP) and ERK1/2 (extracellular signal-regulated kinases 1/2) activation. We determined that Ucn-1 shifted cell death from necrosis to apoptosis and activated caspases 9 and 3/7. Furthermore, mini-array, RT-qPCR and protein analyses of apoptotic genes showed that Ucn-1 upregulated the expression of CD40lg, Xiap and BAD in cells undergoing I/R, involving Epac2 and ERK1/2 activation.
  
  
  CONCLUSIONS
  Our data indicate that Ucn-1 efficiently protected hearts from I/R damage by increasing the cell survival and stimulated apoptotic genes, CD40lg, Xiap and BAD, overexpression through the activation of Epac2 and ERK1/2.
authors: Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, HUVR/Universidad de Sevilla/CSIC, Seville, Spain.
authors: Eva
authors: E
authors: Calderón-Sánchez
authors: Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, HUVR/Universidad de Sevilla/CSIC, Seville, Spain.
authors: Ignacio
authors: I
authors: Díaz
authors: Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, HUVR/Universidad de Sevilla/CSIC, Seville, Spain.
authors: Antonio
authors: A
authors: Ordóñez
authors: Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, HUVR/Universidad de Sevilla/CSIC, Seville, Spain.|Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain.
authors: Tarik
authors: T
authors: Smani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D054832:Urocortins / Q000378:metabolism* / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D020662:Guanine Nucleotide Exchange Factors; C531571:Rapgef4 protein, rat; D054832:Urocortins; D051636:X-Linked Inhibitor of Apoptosis Protein; D023201:CD40 Ligand; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020169:Caspases