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Articles in PresS, published online ahead of print October 10, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00708.2002
Submitted on August 22, 2002
Accepted on October 7, 2002
1 Department of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: pschumac{at}medicine.bsd.uchicago.edu.
Ischemia/reperfusion injury induces cell death, but the mechanisms that are critical for causing cell death are not known. We sought to clarify the relationship between mitochondrial depolarization and cell death using an in vitro model of simulated ischemia and reperfusion.
Spontaneously contracting embryonic cardiomyocytes were subjected to 60 min of ischemia followed by 3 hr reperfusion in a flow-through chamber. Mitochondrial potential (
m ) was assessed using the fluorophore tetramethylrhodamine methyl ester (TMRE). During ischemia,
m decreased to 24±5.5% of baseline, but no recovery was evident during reperfusion. Cell death assessed by Sytox Green dye was minimal during ischemia but averaged 66±7% after 3 hr reperfusion. Cyclosporin A (0.2-0.5 µM), an inhibitor of the mitochondrial permeability transition pore, failed to ameliorate this response. However, the antioxidants N-acetylcysteine(0.5 mM), 2-mercaptopropionyl glycine (0.4 mM), pyrrolidine dithiocarbamate (10 µM) and 1,10 phenanthroline (10 µM) each attenuated the fall in m during ischemia and cell death after reperfusion. Cell death was also attenuated when residual O2 was scavenged enzymatically from the ischemic perfusate, thus creating anoxic ischemia. These results suggested that ROS were important contributors to the decrease in [[DELTA}}m during ischemia. To quantify lipid peroxidation, cells were labeled with C11-BODIPY. Increases in fluorescence observed during ischemia were attenuated by administration of antioxidants or the mitochondrial inhibitor myxothiazol, supporting the conclusion that ROS originating from the electron transport chain contribute to lipid peroxidation during ischemia. Finally, 143B osteosarcoma cells lacking a mitochondrial electron transport chain failed to demonstrate a depletion of m during ischemia and were significantly protected against cell death during reperfusion. Collectively, these studies identify a central role for mitochondrial ROS generation during ischemia in the mitochondrial depolarization and subsequent cell death induced by ischemia and reperfusion in this model.
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