Mitochondrial permeability transition and cytochrome c release in ischemia-reperfusion injury of the rat liver |
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Authors: | Hirakawa Akihiko Takeyama Naoshi Nakatani Toshio Tanaka Takaya |
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Affiliation: | Department of Emergency and Critical Care Medicine, Kansai Medical University, Moriguchi, Osaka, Japan. takeyama@takii.kmu.ac.jp |
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Abstract: | BACKGROUND: We investigated whether ischemia-reperfusion causes activation of caspases and whether this activation is related to cytochrome c release from the mitochondria into the cytosol as a result of the mitochondrial inner membrane permeability transition. MATERIALS AND METHODS: Rats were subjected to 30 min to 120 min of hepatic ischemia followed by 6 h of reperfusion. Cyclosporin A or ruthenium red (inhibitors of the mitochondrial inner membrane permeability transition) was given intravenously at 60 and 30 min before ischemia, respectively. RESULTS: Reperfusion after ischemia caused the release of liver enzymes accompanied by mitochondrial membrane depolarization, DNA fragmentation, and translocation of cytochrome c from the mitochondria into the cytosol. Accumulation of cytochrome c in the cytosol and activation of caspase-3-like protease was already detected during ischemia and before reperfusion. Pretreatment with cyclosporin A or ruthenium red significantly ameliorated the loss of the mitochondrial membrane potential, the increase of plasma membrane permeability, the cytosolic accumulation of cytochrome c, DNA fragmentation, and caspase-3-like protease activation. CONCLUSIONS: The mitochondrial inner membrane permeability transition occurs during ischemia and/or after reperfusion, resulting in translocation of cytochrome c and activation of caspases. |
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Keywords: | apoptosis cyclosporin A ruthenium red caspase-3 mitochondrial membrane potential |
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