Cyclosporine preserves mitochondrial morphology after myocardial ischemia/reperfusion independent of calcineurin inhibition.
BACKGROUND
Opening of the mitochondrial permeability transition pore (MPTP) has been shown to contribute to myocardial ischemia/reperfusion injury. We sought to demonstrate that the myocardial protective effect of inhibiting MPTP opening with cyclosporine A (CsA) results in stabilization of mitochondrial morphology and is independent of CsA-induced calcineurin inhibition.


METHODS
Thirty-seven rabbits were divided into three groups: control (n = 15), CsA (MPTP and calcineurin inhibitor, n = 12), or FK506 (calcineurin inhibitor, n = 10). Each group received a 1-hour infusion of either a saline vehicle, 25 mg/kg CsA or 1 mg/kg FK506. All animals underwent 30 minutes of regional ischemia and 3 hours of reperfusion. Myocardial infarct size was determined using Evans blue dye and triphenyltetrazolium chloride. In situ oligo ligation was used to assess apoptotic cell death. Transmission electron microscopy was used to quantitatively evaluate morphologic differences in the mitochondria between groups.


RESULTS
Infarct size in the CsA group (39% +/- 3%) was significantly reduced compared with the control group (60% +/- 2%, p < 0.001) and FK506 group (55% +/- 3%, p = 0.001). Apoptotic cell death was also attenuated in the CsA group (1.2% +/- 0.5%) compared with the control group (4.3% +/- 0.8%, p = 0.01) and FK506 group (4.1% +/- 0.9%, p = 0.05). Transmission electron microscopy revealed a preservation of normal mitochondrial morphology and a reduction in the percentage of disrupted mitochondria in the CsA group (20% +/- 7%) compared with the control group (53% +/- 12%) and FK506 group (47% +/- 9%).


CONCLUSIONS
Cyclosporine A-induced MPTP inhibition preserves mitochondrial morphology after myocardial ischemia/reperfusion and limits myocyte necrosis and apoptosis. These effects are independent of calcineurin inhibition.
Leshnower
Bradley G
BG
Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19036, USA.
Kanemoto
Shinya
S
Matsubara
Muneaki
M
Sakamoto
Hiroaki
H
Hinmon
Robin
R
Gorman
Joseph H
JH
Gorman
Robert C
RC
D000704:Analysis of Variance; D000818:Animals; D019703:Calcineurin / Q000187:drug effects / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D015425:Myocardial Reperfusion / Q000379:methods; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D011336:Probability; D011817:Rabbits; D011897:Random Allocation; D012680:Sensitivity and Specificity; D016559:Tacrolimus / Q000494:pharmacology
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus