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Link Between Immune Cell Infiltration and Mitochondria‐Induced Cardiomyocyte Death During Acute Cardiac Graft Rejection
Author(s) -
Gomez L.,
Raisky O.,
Chalabreysse L.,
Verschelde C.,
BonnefoyBerard N.,
Ovize M.
Publication year - 2006
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2005.01219.x
Subject(s) - medicine , immune system , infiltration (hvac) , graft rejection , cardiac cell , cardiology , programmed cell death , mitochondrion , cell , immunology , transplantation , apoptosis , microbiology and biotechnology , biochemistry , physics , genetics , biology , thermodynamics , chemistry
Acute cardiac graft rejection (ACGR) is associated with cardiomyocyte apoptosis. We investigated the respective role of the Fas/FasL and mitochondrial permeability transition pore (mPTP) pathways in cardiomyocyte apoptosis accompanying ACGR. Heterotopic cardiac transplantations were performed in 7–9‐week old C57BL6 or C3H mice. Wild type or Fas‐deficient (lpr) mice underwent syngeneic (GS) or allogeneic (GA) transplantation, and received either saline or NIM811, a specific inhibitor of the mPTP. At day 5, we assessed ACGR by histology, cardiomyocyte apoptosis by caspase‐3 activity and cytochrome c release, Ca 2+ ‐induced mPTP opening by a potentiometric approach, and expression of Fas, FasL, TNFα, perforin, granzyme using RT‐PCR. Myocardial infiltration of CD8 + T lymphocytes was performed by immunohistochemistry. Allogenic transplantation increased infiltration of inflammatory cells, upregulated FasL, perforin, granzyme, and TNFα, favored Ca 2+ ‐induced mPTP opening and increased caspase‐3 activity and cytochrome c release in WT grafts. NIM811, but not Fas‐deficiency, significantly reduced all these effects. NIM811 also limited infiltration of CD8 + into WT and lpr transplants. These data suggest that the mPTP pathway plays a major role in cardiomyocyte apoptosis associated with ACGR. Inhibition of mPTP opening may attenuate cardiomyocyte apoptosis either directly or indirectly via a limitation of CD8 + T‐cell activation.