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P. S. Mettu, R. Maddala, D. L. Epstein, P. V. Rao; Effects of Lovastatin on the Gene Expression Profile of Human Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4858.
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The cholesterol-lowering statin agents have been shown to lower intraocular pressure and are associated with a reduced risk of open angle glaucoma. To further explore their pleiotropic effects, we investigated the effects of lovastatin on the gene expression profile in the model system of human trabecular meshwork (HTM) cells.
Confluent cultures of HTM cells obtained from two distinct human cadaveric donors were treated with lovastatin (30 µM) for a period of 24 hours in the presence of 1% serum. Total RNA derived from lovastatin-treated and control HTM cells was subjected to cDNA microarray analysis using spotted oligonucleotide arrays (Operon Human Genome Oligo Set, Version 4.0), which includes approximately 40,000 gene transcripts. GeneSpring GX 10 software was used to perform data analysis. A threshold of 3-fold change in expression in lovastatin-treated HTM cells relative to control was considered significant. Additionally, lovastatin-induced effects on cell morphology and actin cytoskeletal organization were evaluated with standard methods.
cDNA microarray analysis of RNA extracted from HTM cells treated with lovastatin revealed decreased expression in many genes, including C-reactive protein, complement factor H-related proteins 2 and 4, amyloid beta precursor protein, thromboxane-A synthase, MAdCAM-1, BMP-3, fibronectin type III domain, vinculin, myosin light chain, Grb-2 adaptor protein, focal adhesion kinase-associated GTPase regulator, and phosphodiesterase 6G, relative to control HTM cells. Microarray analysis also demonstrated increased expression in lovastatin-treated HTM cells of genes encoding for vasoactive intestinal peptide, semaphorin 3D, integrin -8, SRC-family associated phosphoprotein, -1B adrenergic receptor, guanylate cyclase activator 1A, geranylgeranyl pyrophosphate synthetase, ubiquitin specific protease, and inducible nitric oxide synthase, as compared to controls. These changes in gene expression profile were associated with changes in cell shape and decreased actin stress fibers and focal adhesions in drug treated HTM cells.
Lovastatin modulates the expression of genes encoding proteins known to have significant roles in the cellular inflammatory response, cytoskeletal organization, ECM production and turnover, ion channel activity, and oxidative stress, as observed in the model system of HTM cells. Such effects suggest potential mechanisms by which statin agents may provide therapeutic benefit in chronic diseases such as glaucoma.
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