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Mitochondrial Permeability Transition in Cardiomyocyte Apoptosis during Acute Graft Rejection
Author(s) -
Raisky Olivier,
Gomez L.,
Chalabreysse L.,
GateauRoesch O.,
Loufouat J.,
ThivoletBéjui F.,
Ninet J.,
Ovize M.
Publication year - 2004
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.1600-6143.2004.00473.x
Subject(s) - syngenic , mitochondrial permeability transition pore , apoptosis , necroptosis , transplantation , medicine , tunel assay , programmed cell death , caspase 8 , caspase , cancer research , pharmacology , chemistry , biochemistry
Evidence indicates that acute cardiac graft rejection is associated with cardiomyocyte apoptosis. Mitochondrial permeability transition (MPT) induces apoptotic cell death. We sought to determine whether MPT might play a role in cardiomyocyte apoptosis in the rat model of heterotopic cardiac transplantation. Syngenic and allogenic transplantations were performed, and both native and grafted hearts were harvested 3 or 5 d after transplantation for detection of acute rejection, assessment of Ca 2+ ‐induced MPT, and myocardial apoptosis by TUNEL staining and caspase 3 activity. Allogenic grafts developed severe acute rejection at day 5 with concomitant cardiomyocyte apoptosis (apoptotic index: 7.1 ± 1.0% vs. 1.0 ± 0.2% in syngenic hearts, and caspase 3 activity: 38 ± 25 vs. 5 ± 9 nmol/mg, in allogenic vs. syngenic grafts, respectively). At day 5, Ca 2+ ‐induced MPT was dramatically altered in allogenic when compared with syngenic grafts (mean Ca 2+ overload averaged 0 ± 20 vs. 280 ± 30 μM in allogenic and syngenic grafts, respectively). NIM811, a nonimmunosuppressive derivative of cyclosporin A (CsA), that specifically inhibits the MPT pore, did not alter acute rejection, but significantly delayed Ca 2+ ‐induced MPT pore opening, attenuated caspase 3 activity and cardiomyocyte apoptosis in allogenic grafts. This suggests that mitochondrial permeability transition pore opening may play an important role in cardiomyocyte apoptosis associated with acute cardiac graft rejection.