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K. A. Cook, K. G. Howell, M. P. Fautsch; Differential Gene Expression in Bimataprost Treated Human Primary Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1616.
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Bimatoprost, an ethyl amide prostaglandin F2-alpha analogue (prostamide), increases outflow facility through the uveoscleral and conventional (trabecular) pathways. Unlike other prostaglandin analogues that increase outflow facility, bimatoprost has unique pharmacological activity. We examined primary human trabecular meshwork cells following treatment with bimatoprost to identify molecular targets.
Three independent confluent primary human trabecular meshwork cell lines were incubated with Dulbecco’s Modified Eagle’s Media alone or containing either bimatoprost (1µM) or bimatoprost-free acid (1µM; BFA). Following 24-hour and 72-hour incubations (fresh drug added daily), total RNA was isolated from each cell line and condition. Total RNA (100 ng) was amplified, processed into cRNA, and used to probe Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Partek Genomics Suite (Partek, Inc.) and MetaCore (GeneGo, Inc.) software was used to analyze microarray data. Genes with at least a 1.5-fold change in expression were used in the analysis.
Bimatoprost and BFA significantly altered gene expression in primary monolayer trabecular cells when compared to control. Of the 182 sequences that were differentially expressed at 24 and 72 hours in bimatoprost treatment, 134 of these sequences were also differentially expressed in BFA. Sequences involved in cellular processes regulating signal transduction and gene transcription were affected. Molecules such as TGF-β2, TNF, IGF-1, HGF, c-fos, and c-jun all had a decrease in gene expression. Histone deacetylase, involved in transcription repression, had an increase in gene expression. Molecules involved in the Ras-signaling pathway were also affected.
Bimatoprost and BFA treated human trabecular cells produce a unique molecular profile that differs from cells cultured in media alone. Genes involved in transcription regulation were decreased suggesting a role of bimatoprost in regulating gene expression. Comparison of bimatoprost’s gene expression profile to profiles obtained from other intraocular pressure lowering drugs may identify unique pathways that are important for its pharmacological affects on trabecular meshwork cells.
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