title: Platelet-derived Growth Factor-B Protects Rat Cardiac Allografts From Ischemia-reperfusion Injury.
abstract: BACKGROUND
  Microvascular dysfunction and cardiomyocyte injury are hallmarks of ischemia-reperfusion injury (IRI) after heart transplantation. Platelet-derived growth factors (PDGF) have an ambiguous role in this deleterious cascade. On one hand, PDGF may exert vascular stabilizing and antiapoptotic actions through endothelial-pericyte and endothelial-cardiomyocyte crosstalk in the heart; and on the other hand, PDGF signaling mediates neointimal formation and exacerbates chronic rejection in cardiac allografts. The balance between these potentially harmful and beneficial actions determines the final outcome of cardiac allografts.
  
  
  RESULTS
  We transplanted cardiac allografts from Dark Agouti rat and Balb mouse donors to fully major histocompatibility complex-mismatched Wistar Furth rat or C57 mouse recipients with a clinically relevant 2-hour cold ischemia and 1-hour warm ischemia. Ex vivo intracoronary delivery of adenovirus-mediated gene transfer of recombinant human PDGF-BB upregulated messenger RNA expression of anti-mesenchymal transition and survival factors BMP-7 and Bcl-2 and preserved capillary density in rat cardiac allografts at day 10. In mouse cardiac allografts PDGF receptor-β, but not -α intragraft messenger RNA levels were reduced and capillary protein localization was lost during IRI. The PDGF receptor tyrosine kinase inhibitor imatinib mesylate and a monoclonal antibody against PDGF receptor-α enhanced myocardial damage evidenced by serum cardiac troponin T release in the rat and mouse cardiac allografts 6 hours after reperfusion, respectively. Moreover, imatinib mesylate enhanced rat cardiac allograft vasculopathy, cardiac fibrosis, and late allograft loss at day 56.
  
  
  CONCLUSIONS
  Our results suggest that PDGF-B signaling may play a role in endothelial and cardiomyocyte recovery from IRI after heart transplantation.
authors.affiliation: 1 Transplantation Laboratory, University of Helsinki, Helsinki, Finland. 2 Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany. 3 Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland. 4 Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Tuuminen
authors.forename: Alexey
authors.initials: A
authors.lastname: Dashkevich
authors.forename: Mikko A I
authors.initials: MA
authors.lastname: Keränen
authors.forename: Alireza
authors.initials: A
authors.lastname: Raissadati
authors.forename: Rainer
authors.initials: R
authors.lastname: Krebs
authors.forename: Janne J
authors.initials: JJ
authors.lastname: Jokinen
authors.forename: Ralica
authors.initials: R
authors.lastname: Arnaudova
authors.forename: Eeva
authors.initials: E
authors.lastname: Rouvinen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Antti I
authors.initials: AI
authors.lastname: Nykänen
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D064591:Allografts; D000818:Animals; D000077214:Becaplermin; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016027:Heart Transplantation / Q000009:adverse effects*; D000068877:Imatinib Mesylate / Q000494:pharmacology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis* / Q000235:genetics; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor