Activator protein-2α mediates carbon monoxide-induced stromal cell-derived factor-1α expression and vascularization in ischemic heart

Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):785-94. doi: 10.1161/ATVBAHA.112.301143. Epub 2013 Feb 7.


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.

Approach and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Animals, Newborn
  • Binding Sites
  • Carbon Dioxide / administration & dosage
  • Carbon Dioxide / metabolism
  • Carbon Dioxide / pharmacology*
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / metabolism
  • Cardiotonic Agents / pharmacology*
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism*
  • Chromatin Immunoprecipitation
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electrophoretic Mobility Shift Assay
  • Enzyme Activation
  • HeLa Cells
  • Heme Oxygenase-1 / deficiency
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Hemodynamics / drug effects
  • Humans
  • Immunohistochemistry
  • Injections, Intravenous
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction / diagnostic imaging
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / physiopathology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Neovascularization, Physiologic / drug effects*
  • Organometallic Compounds / administration & dosage
  • Organometallic Compounds / metabolism
  • Organometallic Compounds / pharmacology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Time Factors
  • Transcription Factor AP-2 / genetics
  • Transcription Factor AP-2 / metabolism*
  • Transfection
  • Ultrasonography
  • Up-Regulation
  • Ventricular Function, Left / drug effects


  • CXCL12 protein, rat
  • Cardiotonic Agents
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Membrane Proteins
  • Organometallic Compounds
  • RNA, Messenger
  • TFAP2A protein, human
  • Transcription Factor AP-2
  • tricarbonyldichlororuthenium (II) dimer
  • Carbon Dioxide
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Proto-Oncogene Proteins c-akt