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M. L. Bajenaru, Y. Wang, D. Ivanov, G. Dvoriantchikova, E. Hernandez, J. L. Goldberg, V. I. Shestopalov, M. E. Fini; MMP9-Mediated Retinal Ganglion Cell Apoptosis Involves Disruption Of β1-Integrin Survival Signaling After Retinal Ischemia/Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5841.
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Extracellular matrix (ECM) integrity in the CNS is essential for neuronal homeostasis, and ECM survival signals are transmitted to neurons through the integrin pro-survival signaling pathway. In this study we investigated the role of laminin and integrin signaling pathway in retinal ganglion cells (RGC) survival following retinal ischemia/reperfusion (RIRI) injury and activation of matrix metalloprotease 9 (MMP9).
RIRI was induced in Sprague-Dawley rats by unilateral cannulation of the anterior chamber and elevation of the intraocular pressure (IOP) to 110 mm Hg for 60 min. RGC loss was quantified in the retina after retrograde labeling of RGC with the fluorescent tracers Flourogold and DiA. RGC apoptosis was determined by TUNEL staining in retinal sections. The gelatinolytic activity (MMP-2 and MMP-9) was assayed by in situ zymography with a fluorogenic DQ gelatin substrate. The expression of MMP-9, laminin, β1 integrin, focal adhesion kinase (FAK), and activated FAK-P, was analyzed by immunofluorescence in retinal sections and western blotting in retinal extracts with specific antibodies
β1 integrins and several critical regulators of the integrin survival pathway: FAK, paxillin, vinculin, and talin are expressed in RGC in the adult rat retina. Our analysis indicated that RGC loss in ischemic eyes became apparent at 1 day, and reached 45 % 5 days post-RIRI. RGC apoptosis peaked 1 day post-RIRI. Significant increase in gelatinolytic activity was detected in the retina 1 day post-RIRI and correlated with degradation of laminin from the inner laminar membrane (ILM) and a two-fold decrease in the β1 integrin receptors. In addition dephosphorylation of FAK in RGC was determined by western blotting and immunohistochemistry in the retina 1 day post-RIRI.
Our results suggest that the β1 integrin pro-survival signaling is disrupted in RGC following RIRI, and further emphasize a role for laminin/integrin signaling pathway in neuronal survival.
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