title: Vascular Endothelial Growth Factor-B Overexpressing Hearts Are Not Protected From Transplant-Associated Ischemia-Reperfusion Injury.
abstract: OBJECTIVE
  Cardiac vascular endothelial growth factor-B transgene limits myocardial damage in rat infarction models. We investigated whether heart transplant vascular endothelial growth factor-B overexpression protected against ischemia-reperfusion injury.
  
  
  METHODS
  We transplanted hearts heterotopically from Dark Agouti to Wistar Furth rats. To characterize the role of vascular endothelial growth factor-B in ischemia-reperfusion injury, we transplanted either long-term human vascular endothelial growth factor-B transgene overexpressing hearts from Wistar Furth rats or short-term adeno-associated virus 9-human vascular endothelial growth factor-B-transduced hearts from Dark Agouti rats into Wistar Furth rats. Heart transplants were subjected to 2 hours of cold and 1 hour of warm ex vivo ischemia. Samples were collected 6 hours after reperfusion.
  
  
  RESULTS
  Two hours of cold and 1 hour of warm ischemia increased vascular endothelial growth factor-B mRNA levels 2-fold before transplant and 6 hours after reperfusion. Transgenic vascular endothelial growth factor-B overexpression caused mild cardiac hypertrophy and elevated cardiac troponin T levels 6 hours after reperfusion. Laser Doppler measurements indicated impaired epicardial tissue perfusion in these transgenic transplants. Recombinant human vascular endothelial growth factor-B increased mRNA levels of cytochrome c oxidase and extracellular ATPase CD39, suggesting active oxidative phosphorylation and high ATP production. Adeno-associated virus 9-mediated vascular endothelial growth factor-B overexpression in transplanted hearts increased intragraft macrophages 1.5-fold and proinflammatory cytokine interleukin 12 p35 mRNA 1.6-fold, without affecting recipient serum cardiac troponin T concentration.
  
  
  CONCLUSIONS
  Vascular endothelial growth factor-B expression in transplanted hearts is linked to ischemia and ischemia-reperfusion injury. Cardiac transgenic vascular endothelial growth factor-B overexpression failed to protect heart transplants from ischemia-reperfusion injury.
authors: >From the Transplantation Laboratory, University of Helsinki and Cardiac Surgery, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
authors: Alireza
authors: A
authors: Raissadati
authors: Raimo
authors: R
authors: Tuuminen
authors: Alexey
authors: A
authors: Dashkevich
authors: Maija
authors: M
authors: Bry
authors: Riikka
authors: R
authors: Kivelä
authors: Andrey
authors: A
authors: Anisimov
authors: Simo
authors: S
authors: Syrjälä
authors: Ralica
authors: R
authors: Arnaudova
authors: Eeva
authors: E
authors: Rouvinen
authors: Mikko Ai
authors: MA
authors: Keränen
authors: Rainer
authors: R
authors: Krebs
authors: Antti I
authors: AI
authors: Nykänen
authors: Karl B
authors: KB
authors: Lemström
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D001081:Apyrase / Q000378:metabolism; D050377:Cold Ischemia / Q000009:adverse effects; D003326:Coronary Circulation; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D005822:Genetic Vectors; D016027:Heart Transplantation / Q000009:adverse effects*; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D011920:Rats, Inbred WF; D055647:Rats, Transgenic; D013997:Time Factors; D014161:Transduction, Genetic; D020107:Troponin T / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism*; D052096:Warm Ischemia / Q000009:adverse effects
chemical_list: D015703:Antigens, CD; C508860:Il12a protein, rat; D053765:Interleukin-12 Subunit p35; D020107:Troponin T; C467485:VEGFB protein, human; D042561:Vascular Endothelial Growth Factor B; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D001081:Apyrase; C067869:CD39 antigen