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P. Deng, Y. Peterson, P. Casey, V. Rao; Pharmacological Inhibition of Protein Geranylgeranyltransferase Type I (GGTase–I) by GGTI–DU40 Increases Aqueous Humor Outflow in Perfused Porcine Eyes . Invest. Ophthalmol. Vis. Sci. 2006;47(13):431.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the effects of inhibition of isoprenylation of small GTP–binding proteins such as Rho GTPases and the beta–gamma subunits of heterotrimeric G–proteins such as Galpha12/13 on aqueous humor outflow.
A selective inhibitor of GGTase–I (GGTI–DU40) was tested in this study to investigate its effects on actin cytosketal integrity, cell adhesions, cell–cell junctions, myosin II phosphosphorylation, and membrane localization of Rho, Rap and G–beta/gamma in trabecular meshwork (TM) cells, using immunofluorescence detection and immunobloting analysis. The effects of GGTI–DU40 on aqueous humor outflow were determined using organ cultured, perfused anterior segments of porcine eyes.
GGTI–DU40 treatment induced dose dependent (5 to 40 µM) changes in TM cell morphology, and caused reversible decreases in actin stress fibers and focal adhesions. Myosin light chain phosphorylation was decreased significantly, and membrane localization of Rho, Rap and G–beta/gamma was impaired in drug–treated TM cells. Aqueous outflow facility was increased significantly (by 30%) in eyes (n=8) perfused for 24 to 96 hours with 10 µM GGTI–DU40.
These data demonstrate that inhibition of geranylgeranylation of Rho GTPases and heterotrimeric G–proteins in the aqueous outflow pathway increases aqueous humor outflow, possibly through the tissue relaxation, and through altered cell adhesive interactions and actin cytoskeletal organization in cells of the outflow pathway. This study indicates that the GGTase–I enzyme could serve as a potential molecular target for lowering increased ocular pressure in glaucoma patients.
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