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Mitochondrial Permeability Can Regulate Endothelial Cell Necroptosis and Promote Cardiac Allograft Rejection.

I. Gan,1,2 J. Jiang,1 D. Lian,1 A. Jevnikar,1,3 Z.-X. Zhang.1,2

1Matthew Mailing Centre for Translational Transplant Studies, Western University, London, ON, Canada
2Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
3Department of Medicine, Western University, London, ON, Canada

Meeting: 2017 American Transplant Congress

Abstract number: B14

Keywords: Graft survival, Heart, Rejection, Tumor necrosis factor (TNF)

Session Information

Session Name: Poster Session B: Acute and Chronic Rejection

Session Type: Poster Session

Date: Sunday, April 30, 2017

Session Time: 6:00pm-7:00pm

 Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Background: Transplant injury is invariably associated with programmed cell death (PCD) resulting in organ rejection. Many forms of PCD have been described including apoptosis, pyroptosis, ferroptosis, and necroptosis. They are induced by various death receptors (DRs) including tumor necrosis factor receptor-1 (TNFR1), DR4/5, Fas, and toll-like receptor (TLR) engagement. We were the first to describe receptor-interacting serine/threonine protein kinase 3 (RIPK3) mediated necroptosis in transplant injury. Tissue necrosis, release of HMGB1, and graft rejection were thus attenuated in RIPK3 null allografts following transplantation. Necroptosis leads to mitochondrial fragmentation which can promote cell death. Our goal was to determine whether mitochondrial injury is a consequence or if they participate in necroptotic cardiac cell death and graft rejection.

Methods: In vitro, we induced necroptosis in murine microvascular endothelial cells (MVECs) with TNFα 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 (H-2b) and mitochondrial permeability transition (MPT) deficient Ppif-/- (H-2b) mice were heterotopically transplanted intra-abdominally using allogeneic BALB/c recipient mice (H-2d) with or without rapamycin treatment.

Results: In cultured MVECs, we found that TNFα and caspase-8 inhibition triggered cells to undergo RIPK1- and RIPK3-dependent necroptosis and this cell death was attenuated by MPT inhibition. Ppif deficient cardiac allografts showed no difference in survival compared to wildtype C57BL/6 grafts without rapamycin treatment. However, with rapamycin treatment, Ppif deficient cardiac allografts had prolonged survival compared to wild type grafts (MSD=85 versus 31 days, p<0.0001).

Conclusion: Our studies show that mitochondrial permeability 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, Jevnikar A, Zhang Z.-X. Mitochondrial Permeability Can Regulate Endothelial Cell Necroptosis and Promote Cardiac Allograft Rejection. Am J Transplant. 2017;17 (suppl 3).

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To cite this abstract in AMA style:

Gan I, Jiang J, Lian D, Jevnikar A, Zhang Z-X. Mitochondrial Permeability Can Regulate Endothelial Cell Necroptosis and Promote Cardiac Allograft Rejection. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/mitochondrial-permeability-can-regulate-endothelial-cell-necroptosis-and-promote-cardiac-allograft-rejection/. Accessed May 10, 2025.

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