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T. Inoue, D. L. Epstein, P. V. Rao; Chemical Inhibition of N-WASP, a Regulator of Actin Polymerization Increases Aqueous Humor Outflow in Perfused Porcine Eyes. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1638.
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To determine the effects of chemical inhibition of N-WASP, a regulator of actin nucleation, on aqueous humor outflow.
Wiskostatin, a selective inhibitor of N-WASP was studied to investigate its effects on aqueous outflow facility using enucleated porcine eyes and Grant perfusion system. The effect of Wiskostatin on the activation of N-WASP was evaluated by determining the membrane localization of N-WASP in cultured trabecular meshwork (TM) cells through immunoblot analysis. Changes in cell shape, actin cytoskeletal integrity and cell adhesions were assessed in TM cells treated with Wiskostatin by immunocytochemical analysis.
Aqueous outflow facility was observed to increase progressively and significantly by 24% and 44% over the sham-treated control eyes following the 50 µM Wiskostatin perfusion at one hour and 5 hours, respectively. Membrane localization of N-WASP was impaired in Wiskostatin-treated TM cells. The Wiskostatin treated TM cells demonstrated extensive vacuoles in their cytosol, and both actin stress fibers and focal adhesions were markedly decreased in a reversible manner.
These data indicate that chemical inhibition of N-WASP increases aqueous humor outflow, possibly by altered cell adhesive interactions and actin cytoskeletal organization in cells of the outflow pathway. This study suggests that N-WASP could be a potential molecular target for novel drug therapy to lower intraocular pressure in glaucoma patients.
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