Abstract 14929: The Role Of Mitochondrial Permeability Transition In Reperfusion-induced Cardiomyocyte Death Depends On The Duration Of Ischemia
Mitochondrial permeability transition (MPT) is critical in cardiomyocyte death during reperfusion but it is not the only mechanism responsible for cell injury.
Objectives: To investigate the role of the duration of myocardial ischemia on mitochondrial integrity and cardiomyocyte death.
Methods and Results: Mitochondrial membrane potential (ΔΨm, JC-1) and MPT (calcein) were studied in cardiomyocytes from wild-type and cyclophilin D (CyD) KO mice refractory to MPT, submitted to ischemia and reperfusion. Reperfusion after 15min ischemia induced a rapid recovery of ΔΨm, extreme cell shortening (contracture) and mitochondrial calcein release, and CyD ablation did not affect these changes or cell death. However, when reperfusion was performed after 25min ischemia, CyD ablation improved ΔΨm recovery and reduced calcein release and cell death (57.8±4.9% vs 77.3±4.8%, p<0.01). In a Langendorff system, CyD ablation paradoxically increased infarct size after 30min of ischemia (61.3±6.4% vs 45.3±4.0%, p=0.02) but reduced it when ischemia was prolonged to 60min (52.8±8.1% vs 87.6±3.7%, p<0.01). NMR spectroscopy in rat hearts showed a rapid recovery of phosphocreatine after 30min ischemia followed by a marked decay associated with contracture and LDH release, that were preventable with contractile blockade but not with cyclosporine A. In contrast, after 50min ischemia, phosphocreatine recovery was impaired even with contractile blockade (65.2±4% at 2 min), and cyclosporin A reduced contracture, LDH release and infarct size (52.1±4.2% vs 82.8±3.6%, p<0.01).
Conclusions: The duration of ischemia critically determines the importance of MPT on reperfusion injury. Mechanisms other than MPT may play an important role in cell death after less severe ischemia.
- © 2011 by American Heart Association, Inc.