title: Mitochondrial permeability transition in cardiomyocyte apoptosis during acute graft rejection.
abstract: 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.
authors.affiliation: Service de Chirurgie Thoracique, Hôpital L Pradel, 59, Bd Pinel, 69394 Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Raisky
authors.forename: L
authors.initials: L
authors.lastname: Gomez
authors.forename: L
authors.initials: L
authors.lastname: Chalabreysse
authors.forename: O
authors.initials: O
authors.lastname: Gateau-Roesch
authors.forename: J
authors.initials: J
authors.lastname: Loufouat
authors.forename: F
authors.initials: F
authors.lastname: Thivolet-Béjui
authors.forename: J
authors.initials: J
authors.lastname: Ninet
authors.forename: M
authors.initials: M
authors.lastname: Ovize
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D053938:DNA Fragmentation; D006084:Graft Rejection; D016027:Heart Transplantation / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D010539:Permeability; D051381:Rats; D011917:Rats, Inbred Lew; D013367:Submitochondrial Particles / Q000378:metabolism; D013997:Time Factors; D014180:Transplantation
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium