Vascular Endothelial Growth Factor-B Overexpressing Hearts Are Not Protected From Transplant-Associated Ischemia-Reperfusion Injury

Exp Clin Transplant. 2017 Apr;15(2):203-212. doi: 10.6002/ect.2016.0181. Epub 2016 Sep 1.

Abstract

Objectives: 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.

Materials and 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.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antigens, CD / metabolism
  • Apoptosis
  • Apyrase / metabolism
  • Cold Ischemia / adverse effects
  • Coronary Circulation
  • Dependovirus / genetics
  • Disease Models, Animal
  • Electron Transport Complex IV / metabolism
  • Genetic Vectors
  • Heart Transplantation / adverse effects*
  • Interleukin-12 Subunit p35 / genetics
  • Interleukin-12 Subunit p35 / metabolism
  • Macrophages / metabolism
  • Male
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Oxidative Phosphorylation
  • Rats, Inbred WF
  • Rats, Transgenic
  • Time Factors
  • Transduction, Genetic
  • Troponin T / metabolism
  • Vascular Endothelial Growth Factor B / genetics
  • Vascular Endothelial Growth Factor B / metabolism*
  • Warm Ischemia / adverse effects

Substances

  • Antigens, CD
  • Il12a protein, rat
  • Interleukin-12 Subunit p35
  • Troponin T
  • VEGFB protein, human
  • Vascular Endothelial Growth Factor B
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • Apyrase
  • CD39 antigen