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Permanent cerebral ischemia induces sustained procaspase 9L increase not controlled by Bcl-2

Pfister, Y
Vallet, P G
Published in Brain Research. 2003, vol. 966, no. 1, p. 26-39
Abstract We have investigated how transgenic overexpression of human Bcl-2 (Hu-Bcl-2) modifies cell death proteins activation in the long-term in a model of permanent cerebral ischemia induced by middle cerebral artery occlusion. Hu-Bcl-2, cytochrome c, caspases 9 and 3 expression were examined by immunoblotting and immunohistochemistry. In wild type mice, 1 day after middle cerebral artery occlusion, cytochrome c released from the mitochondria was detected. Middle cerebral artery occlusion induces a lasting activation of caspases in WT mice from day 3 post-injury. Increased level of caspase 3 is accompanied by a decrease in procaspase 3. In contrast, middle cerebral artery occlusion induced a sustained increase of procaspase 9L and a decrease in procaspase 9S concomitant to caspase 9 production. These events were observed in the operated but not in the unoperated hemisphere. Bcl-2 overexpression blocks cytochrome c release and delays caspases activation. Consequently procaspase 3 decrease was no more observed. However, Bcl-2 overexpression did not influence the middle cerebral artery occlusion-induced changes in procaspases 9 L and S. Fourteen days after middle cerebral artery occlusion the apoptotic cascade was no longer blocked in transgenic mice. Caspases 9 and 3 were increased, procaspase 3 was decreased but procaspase 9L and procaspase 9S remained increased and decreased respectively. Hu-Bcl-2 overexpression delays the activation of the cell death molecular machinery but does not control the ischemia-induced change in procaspase 9 L and S. Procaspase 9L increase is a potentially harmful event threatening cells of a rapid destruction when anti-apoptotic treatments by Bcl-2, or caspases inhibitors, are overrun.
Keywords AnimalsBrain Ischemia/metabolismCaspase 9Caspases/analysis/biosynthesisCerebral Cortex/chemistry/metabolismEnzyme Induction/physiologyEnzyme Precursors/analysis/biosynthesisGene Expression Regulation, Enzymologic/physiologyHumansMaleMiceMice, Inbred C57BLMice, TransgenicProto-Oncogene Proteins c-bcl-2/biosynthesis/genetics
PMID: 12646305
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PFISTER, Y et al. Permanent cerebral ischemia induces sustained procaspase 9L increase not controlled by Bcl-2. In: Brain Research, 2003, vol. 966, n° 1, p. 26-39. https://archive-ouverte.unige.ch/unige:26600

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Deposited on : 2013-03-06

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