Mitochondrial Membrane Permeability Plays a Critical Role for Endothelial Cell Necroptosis and Cardiac Allograft Rejection

I. Gan, J. Jiang, D. Lian, X. Huang, W. Liu, A. Haig, A. Jevnikar, Z. Zhang.

Matthew Mailing Centre for Translational Transplant Studies, University of Western Ontario, London, ON, Canada
Multi Organ Transplant Program, London Health Sciences Centre, London, ON, Canada
Pathology and Laboratory Medicine, University of Western Ontario, London, ON, Canada
Medicine, University of Western Ontario, London, ON, Canada.

Meeting: 2018 American Transplant Congress

Abstract number: A396

Keywords: Endothelial cells, Heart, Necrosis

Session Information

Session Name: Poster Session A: Tolerance / Immune Deviation

Session Type: Poster Session

Date: Saturday, June 2, 2018

Session Time: 5:30pm-7:30pm

Presentation Time: 5:30pm-7:30pm

Location: Hall 4EF

Background: Transplant injury is invariably associated with programmed cell death resulting in delayed graft function and organ rejection. We were the first to describe receptor-interacting serine/threonine protein kinase 3 (RIPK3) mediated necroptosis in transplant injury, where tissue necrosis and graft rejection were attenuated in RIPK3 null kidney and heart allografts following transplantation. Until now, the effect of mitochondrial dysfunction in the necroptotic pathway remains controversial – it is suggested that mitochondrial dysfunction may promote necroptosis in some studies but not in others. Here, our goal was to determine if mitochondrial dysfunction participates in cardiac cell necroptotic death and accelerates graft rejection.

Methods: In vitro, we induced necroptosis in murine microvascular endothelial cells (MVECs) withTNFα and caspase-8 inhibitor. Necrotic cell death was measured using Sytox Green nucleic acid staining and quantified with the Essen Bioscience Incucyte Zoom live cell imaging.

In vivo, cardiac grafts from wildtype C57BL/6 and mitochondrial permeability transition (MPT) deficient (Cyp-D^-/-) mice were heterotopically transplanted into allogeneic BALB/c mice followed by rapamycin treatment.

Results: TNFα triggered cells to undergo RIPK1- and RIPK3-dependent necroptosis under caspase-8 inhibition. Interestingly, inhibition of MPT could also inhibit cell necroptotic death. MPT is largely regulated by Cyclophilin-D (Cyp-D). Cyp-D deficiency or RNA silencing protected MVEC from necroptosis. In vivo, Cyp-D-deficient cardiac allografts showed prolonged survival in allogeneic BALB/c mice (n=7, >100d) compared to wild type C57BL/6 grafts (n=7, <40d, p<0.0001) post transplantation.

Conclusion: Our studies show that MPT may be an important mechanistic mediator of necroptosis in MVECs, and targeting mitochondria-mediated cell death to reduce cardiac graft rejection has therapeutic potential.

CITATION INFORMATION: Gan I., Jiang J., Lian D., Huang X., Liu W., Haig A., Jevnikar A., Zhang Z. Mitochondrial Membrane Permeability Plays a Critical Role for Endothelial Cell Necroptosis and Cardiac Allograft Rejection Am J Transplant. 2017;17 (suppl 3).

To cite this abstract in AMA style:

Gan I, Jiang J, Lian D, Huang X, Liu W, Haig A, Jevnikar A, Zhang Z. Mitochondrial Membrane Permeability Plays a Critical Role for Endothelial Cell Necroptosis and Cardiac Allograft Rejection [abstract]. https://atcmeetingabstracts.com/abstract/mitochondrial-membrane-permeability-plays-a-critical-role-for-endothelial-cell-necroptosis-and-cardiac-allograft-rejection/. Accessed November 21, 2024.

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