title: CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury.
abstract: OBJECTIVE
  Previous studies of ischemia-reperfusion injury (IRI) in hearts from mice with cardiac-restricted overexpression of CCN2 have shown that CCN2 increases tolerance towards IRI. The objectives of this study were to investigate to what extent post-ischemic administration of recombinant human CCN2 (rhCCN2) would limit infarct size and improve functional recovery and what signaling pathways are involved.
  
  
  METHODS
  Isolated mice hearts were perfused ad modum Langendorff, subjected to no-flow, global ischemia, and subsequently, exposed to mammalian cell derived, full-length (38-40kDa) rhCCN2 (250 nM) or vehicle during the first 15 min of a 60 min reperfusion period.
  
  
  RESULTS
  Post-ischemic administration of rhCCN2 resulted in attenuation of infarct size from 58 ± 4% to 34 ± 2% (p < 0.001) which was abrogated by concomitant administration of the PI3 kinase inhibitor LY294002 (45 ± 3% vs. 50 ± 3%, ns). In congruence with reduction of infarct size rhCCN2 also improved recovery of left ventricular developed pressure (p < 0.05). Western blot analyses of extracts of ex vivo-perfused murine hearts also revealed that rhCCN2 evoked concentration-dependent increase of cardiac phospho-GSK3β (serine-9) contents.
  
  
  CONCLUSIONS
  We demonstrate that post-ischemic administration of rhCCN2 increases the tolerance of ex vivo-perfused murine hearts to IRI. Mechanistically, this postconditioning effect of rhCCN2 appeared to be mediated by activation of the reperfusion injury salvage kinase pathway as demonstrated by sensitivity to PI3 kinase inhibition and increased CCN2-induced phosphorylation of GSK3β (Ser-9). Thus, the rationale for testing rhCCN2-mediated post-ischemic conditioning of the heart in more complex models is established.
authors.affiliation: Institute for Surgical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Ole Jørgen
authors.initials: OJ
authors.lastname: Kaasbøll
authors.affiliation: Institute for Surgical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Ingvild Tronstad
authors.initials: IT
authors.lastname: Moe
authors.affiliation: Institute for Surgical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Mohammad Shakil
authors.initials: MS
authors.lastname: Ahmed
authors.affiliation: Dept. of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Stang
authors.affiliation: Institute for Surgical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Else Marie Valbjørn
authors.initials: EM
authors.lastname: Hagelin
authors.affiliation: Institute for Surgical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000627:therapeutic use; D055513:Connective Tissue Growth Factor / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects*; D006801:Humans; D057775:Ischemic Postconditioning / Q000379:methods; D008297:Male; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000627:therapeutic use; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: C526317:CCN2 protein, human; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011994:Recombinant Proteins; D055513:Connective Tissue Growth Factor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3