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Vascular Endothelial Growth Factor-B Overexpressing Hearts Are Not Protected From Transplant-Associated
Alireza Raissadati1, Raimo Tuuminen, Alexey Dashkevich
1>From the Transplantation Laboratory, University of Helsinki and Cardiac Surgery, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
Insights
Heart transplant vascular endothelial growth factor-B overexpression did not protect against ischemia-reperfusion injury. Increased vascular endothelial growth factor-B levels were linked to transplant injury, not protection.
Area of Science:
- Cardiology
- Transplantation Immunology
- Molecular Biology
Background:
- Vascular Endothelial Growth Factor-B (VEGF-B) has shown protective effects in myocardial infarction models.
- The role of VEGF-B in heart transplantation and ischemia-reperfusion injury (IRI) remains unclear.
Purpose of the Study:
- To investigate whether VEGF-B overexpression in transplanted hearts protects against ischemia-reperfusion injury.
- To characterize the effects of VEGF-B on cardiac function and inflammatory responses post-transplant.
Main Methods:
- Heterotopic heart transplantation in rat models (Dark Agouti to Wistar Furth).
- Utilized long-term transgenic VEGF-B overexpressing hearts and short-term adeno-associated virus 9-VEGF-B transduced hearts.
- Subjected transplants to 2 hours cold and 1 hour warm ex vivo ischemia, with samples collected 6 hours post-reperfusion.
Main Results:
- Ischemia and reperfusion increased VEGF-B mRNA levels in transplanted hearts.
- Transgenic VEGF-B overexpression led to cardiac hypertrophy, elevated troponin T, and impaired perfusion.
- Adeno-associated virus 9-mediated VEGF-B increased intragraft macrophages and pro-inflammatory cytokine mRNA without affecting recipient cardiac troponin T.
Conclusions:
- VEGF-B expression in transplanted hearts is associated with ischemia and IRI.
- Cardiac transgenic VEGF-B overexpression failed to provide protection against IRI in heart transplants.
- VEGF-B may play a detrimental role in the context of cardiac IRI post-transplantation.
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.
