Master of Science
Following transplantation, graft rejection continues to be a significant cause of negative patient outcomes. Programmed cell death events are, in turn, significant contributors to the delayed function and rejection of transplanted organs. We have previously demonstrated that inhibition of necroptosis prevents murine microvascular endothelial cell (MVEC) death and can attenuate murine graft rejection. In this study, we examined the mitochondrial permeability transition pore (mPTP) and its regulator molecule, cyclophilin-D (Cyp-D). Opening of the mPT pore triggers apoptotic molecules release and ultimately results in cell death.However, the role of mPTP in the necroptotic pathway and in transplantation rejection remains unclear. Here we found that TNFα triggered MVEC to undergo receptor-interacting protein kinase family (RIPK1/3)-dependent necroptosis. Interestingly, the inhibition of either mPTP opening or Cyp-D protected MVECs from necroptosis; inhibition or deficiency of Cyp-D alone attenuated RIPK3-downstream mixed lineage kinase domain like protein (MLKL) phosphorylation. Furthermore, Cyp-D-deficient cardiac grafts showed prolonged survival in allogeneic BALB/c mice post transplantation in comparison to wild- type grafts. Our study suggests that the mPTP may be an important mechanistic mediator of necroptosis in cardiac grafts, and that targeting its opening via the inhibition of Cyp-D presents therapeutic potential in the mitigation of cell death and cardiac graft rejection.
Gan, Ingrid, "Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection" (2018). Electronic Thesis and Dissertation Repository. 5919.