title: Activator protein-2α mediates carbon monoxide-induced stromal cell-derived factor-1α expression and vascularization in ischemic heart.
abstract: OBJECTIVE
  Increased cardiac stromal cell-derived factor-1α (SDF-1α) expression promotes neovascularization and myocardial repair after ischemic injury through recruiting stem cells and reducing cardiomyocyte death. Previous studies have shown that heme oxygenase-1 and its reaction byproduct, carbon monoxide (CO), induce SDF-1α expression in ischemic heart. However, the mechanism underlying heme oxygenase-1/CO-induced cardiac SDF-1α expression remains elusive. This study aims to investigate the signaling pathway and the transcriptional factor that mediate CO-induced SDF-1α gene expression and cardioprotection.
  
  
  RESULTS
  CO gas and a CO-releasing compound, tricarbonyldichlororuthenium (II) dimer, dose-dependently induced SDF-1α expression in primary neonatal cardiomyocytes and H9C2 cardiomyoblasts. Promoter luciferase-reporter assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation demonstrated that the activator protein 2α (AP-2α) mediated tricarbonyldichlororuthenium (II) dimer-induced SDF-1α gene transcription. Tricarbonyldichlororuthenium (II) dimer induced AP-2α expression via protein kinase B (AKT)-dependent signaling. AKT inhibition or AP-2α knockdown reduced tricarbonyldichlororuthenium (II) dimer-induced SDF-1α expression. Coronary ligation induced transient increases of cardiac AP-2α and SDF-1α expression, which were declined at 1 week postinfarction in mice. Periodic exposure of coronary-ligated mice to CO (250 ppm for 1 hour/day, 6 days) resumed the induction of AP-2α and SDF-1α gene expression in infarcted hearts. Immunohistochemistry and echocardiography performed at 4 weeks after coronary ligation revealed that CO treatment enhanced neovascularization in the myocardium of peri-infarct region and improved cardiac function. CO-mediated SDF-1α expression and cardioprotection was ablated by intramyocardial injection of lentivirus bearing specific short hairpin RNA targeting AP-2α.
  
  
  CONCLUSIONS
  Our data demonstrate that AKT-dependent upregulation of AP-2α is essential for CO-induced SDF-1α expression and myocardial repair after ischemic injury.
authors: Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 115, Taiwan, ROC.
authors: Heng-Huei
authors: HH
authors: Lin
authors: Yen-Hui
authors: YH
authors: Chen
authors: Ming-Tsai
authors: MT
authors: Chiang
authors: Pei-Ling
authors: PL
authors: Huang
authors: Lee-Young
authors: LY
authors: Chau
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002245:Carbon Dioxide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D006367:HeLa Cells; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014463:Ultrasonography; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C575935:CXCL12 protein, rat; D002316:Cardiotonic Agents; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008565:Membrane Proteins; D009942:Organometallic Compounds; D012333:RNA, Messenger; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; C447082:tricarbonyldichlororuthenium (II) dimer; D002245:Carbon Dioxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt