Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Pathology

Supervisor

Dr. Zhuxu Zhang

2nd Supervisor

Dr. Anthony Jevnikar

Joint Supervisor

Abstract

Cell death results in tissue damage and ultimately donor graft rejection and can occur as an active molecular process through apoptotic, necrotic and newly identified Receptor Interacting Protein 1 and 3 kinase (RIPK1/3) mediated necroptotic pathways. Necroptosis leads to the release of inflammatory molecules and activation of immune cells which can potentially threaten the graft and has yet to be studied in cardiac transplantation. We have found that necroptosis was induced in murine cardiac microvascular endothelial cells (MVEC) under anti-apoptotic conditions following TNFa treatment and results in the release of the danger molecule high mobility group box 1 (HMGB1). Necroptosis was inhibited by the RIPK1 inhibiting molecule necrostatin-1 and by genetic deletion of RIPK3. In addition, tissue necrosis, release of HMGB1 and graft cell infiltrate were attenuated in RIPK3 null heart allografts following transplantation. Finally, a brief sirolimus treatment markedly prolonged RIPK3 null cardiac allograft survival in allogeneic BALB/c recipients as compared to wildtype C57BL/6 donor grafts (95+5.8 vs. 24+2.6 days, P


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