HSC College of Pharmacy
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The HSC College of Pharmacy is committed to developing patient-centric pharmacy professionals trained in an interprofessional environment. We advocate a team health care environment coupled with optimizing health through discovery.
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Browsing HSC College of Pharmacy by Author "Bermudez, Jaclyn Y."
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Item HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFbeta2 in the Trabecular Meshwork(ARVO Journals, 2016-07-01) Bermudez, Jaclyn Y.; Webber, Hannah C.; Patel, Gaurang C.; Liu, Xiangyang; Cheng, Yi-Qiang; Clark, Abbot F.; Mao, WeimingPURPOSE: Elevated intraocular pressure (IOP) in primary open-angle glaucoma (POAG) results from glaucomatous damage to the trabecular meshwork (TM). The glaucoma-associated factor TGFbeta2 is increased in aqueous humor and TM of POAG patients. We hypothesize that histone acetylation has a role in dysregulated TGFbeta2 expression. METHODS: Protein acetylation was compared between nonglaucomatous TM (NTM) and glaucomatous TM (GTM) cells using Western immunoblotting (WB). Nonglaucomatous TM cells were treated with 10 nM thailandepsin-A (TDP-A), a potent histone deacetylase inhibitor for 4 days. Total and nuclear proteins, RNA, and nuclear protein-DNA complexes were harvested for WB, quantitative PCR (qPCR), and chromatin immunoprecipitation (ChIP) assays, respectively. Paired bovine eyes were perfused with TDP-A versus DMSO, or TDP-A versus TDP-A plus the TGFbeta pathway inhibitor LY364947 for 5 to 9 days. Intraocular pressure, TM, and perfusate proteins were compared. RESULTS: We found increased acetylated histone 3 and total protein acetylation in the GTM cells and TDP-A treated NTM cells. Chromatin immunoprecipitation assays showed that TDP-A induced histone hyperacetylation associated with the TGFbeta2 promoter. This change of acetylation significantly increased TGFbeta2 mRNA and protein expression in NTM cells. In perfusion-cultured bovine eyes, TDP-A increased TGFbeta2 in the perfusate as well as elevated IOP. Histologic and immunofluorescent analyses showed increased extracellular matrix and cytoskeletal proteins in the TM of TDP-A treated bovine eyes. Cotreatment with the TGFbeta pathway inhibitor LY364947 blocked TDP-A-induced ocular hypertension. CONCLUSIONS: Our results suggest that histone acetylation has an important role in increased expression of the glaucoma-associated factor TGFbeta2. Histone hyperacetylation may be the initiator of glaucomatous damage to the TM.