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Retinal ischemia-induced apoptosis is associated with alteration in Bax and Bcl-x(L) expression rather than modifications in Bak and Bcl-2

Schorderet, Daniel F.
Published in Molecular Vision. 2009, vol. 15, p. 2101-2110
Abstract PURPOSE: Apoptosis is known to play a key role in cell death after retinal ischemia. However, little is known about the kinetics of the signaling pathways involved and their contribution to this process. The aim of this study was to determine whether changes in the expression of molecules in the mitochondrial apoptotic pathway might explain the progression of retinal damage following ischemia/reperfusion. METHODS: Retinal ischemia was induced by elevating intraocular pressure in the vitreous cavity to 150 mmHg for a period of 60 min. At time 0, 3 h (early phase), and 24 h (late phase) after reperfusion, the retinas were harvested and modifications in the expression of Bax, Bak, Bcl-2, and Bcl-x(L) as well as caspase-3 and -7, were examined by qPCR and, in some cases, by western blot. RESULTS: qPCR analysis performed at the early phase after ischemia revealed a time dependent decrease in Bax, Bak, and Bcl-x(L) and no alteration in Bcl-2 mRNA expression in response to retinal ischemia. At the protein level, proapoptotic Bax and Bak were not modulated while Bcl-2 and Bcl-x(L) were significantly upregulated. At this stage, the Bax per Bcl-2 and Bax:Bcl-x(L) ratios were not modified. At the late phase of recovery, Bax and Bcl-x(L) mRNAs were downregulated while Bak was increased. Increased Bax:Bcl-2 and Bax:Bcl-x(L) ratios at both the mRNA and protein levels were observed 24 h after the ischemic insult. Analysis of caspases associated with mitochondria-mediated apoptosis revealed a specific increase in the expression of caspase-3 in the ischemic retinas 24 h after reperfusion, and a decrease in the expression of caspase-7. CONCLUSIONS: This study revealed that Bcl-2-related family members were differently regulated in the early and late phases after an ischemic insult. We showed that the Bax:Bcl-2 and Bax:Bcl-x(L) balances were not affected in the initial phases, but the Bax:Bcl-x(L) ratio shifted toward apoptosis during the late phase of recovery. This shift was reinforced by caspase-3 upregulation.
Keywords Animals*Apoptosis/geneticsCaspase 3/genetics/metabolismCaspase 7/genetics/metabolismGene Expression RegulationIschemia/complications/enzymology/genetics/*pathologyRNA, Messenger/genetics/metabolismRatsRats, Sprague-DawleyReperfusion Injury/complications/enzymology/geneticsRetina/enzymology/*pathologyTime FactorsBcl-2 Homologous Antagonist-Killer Protein/genetics/*metabolismBcl-2-Associated X Protein/genetics/*metabolismBcl-X Protein/genetics/*metabolism
PMID: 19862336
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PRODUIT-ZENGAFFINEN, Nathalie, POURNARAS, Constantin, SCHORDERET, Daniel F. Retinal ischemia-induced apoptosis is associated with alteration in Bax and Bcl-x(L) expression rather than modifications in Bak and Bcl-2. In: Molecular Vision, 2009, vol. 15, p. 2101-2110. https://archive-ouverte.unige.ch/unige:20045

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Deposited on : 2012-04-23

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