Thorac Cardiovasc Surg 2012; 60 - PP129
DOI: 10.1055/s-0031-1297776

PHD (Prolyl-hydroxylase)-inhibitor activating Hypoxia-inducible transcription factors (HIFs) reduces levels of transplant arteriosclerosis in a murine aortic allograft model

C Heim 1, S Aghayeva 1, Z Wang 2, B Motsch 1, N Koch 1, M Weyand 1, W Bernhardt 2, SM Ensminger 1
  • 1Universität Erlangen-Nürnberg, Herzchirurgie, Erlangen, Germany
  • 2Universität Erlangen-Nürnberg, Nephrologie, Erlangen, Germany

Introduction: The development of transplant arteriosclerosis, the hallmark feature of heart transplant rejection is associated with chronic immune response and influenced by the initial injury caused by ischemia and reperfusion. As previously shown, donor treatment with a PHD-inhibitor activating Hypoxia-inducible transcription factors (HIFs) prevents graft injury and prolongs survival in an allogenic kidney transplant model. Therefore, the aim of this study was to investigate the effect of HIF activation with a PHD-inhibitor on transplant arteriosclerosis in an experimental aortic allograft model.

Methods: MHC-class-I mismatched C.B10-H2(b)/LilMcdJ donor aortas were transplanted into BALB/c mice. Donor animals received a single dose of PHD-inhibitor FG-4497 (40mg/kg i.p.) or vehicle 4h before transplantation (n=5). The mice were harvested 30 days after transplantation and grafts were analyzed by histology, morphometry and immunofluorescence.

Results: Donor preconditioning with FG-4497 resulted in HIF accumulation and induction of HIF target genes, which persisted during the entire experimental protocol. Vascular lesions were present in both experimental groups, however there was significantly less intimal proliferation in preconditioned grafts as compared to vehicle treated controls [intimal proliferation 29.8±8% (FG-4497) vs. 72±9% (control)] indicating that activation of Hypoxia-inducible transcription factors (HIFs) and hereby adaptation to low oxygen prevents the development of transplant arteriosclerosis and therefore allograft injury.

Conclusion: These data suggest that activation of Hypoxia-inducible transcription factors (HIFs) plays a crucial role in the development of transplant arteriosclerosis. Pharmaceutical inhibition of PHDs appears to be a very attractive strategy for organ preservation that deserves further clinical evaluation.