Mitochondrial permeability transition in cardiomyocyte apoptosis during acute graft rejection.

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 microM 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.