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John W. Crabb, Xianglin Yuan, John S. Crabb, Tasneem M. Putliwala, Abbot F. Clark, Kathryn E. Bollinger; Quantitative Proteomic Studies Implicate Mitochondrial Dysfunction in the Trabecular Meshwork in Glaucoma Pathology. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6611.
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Toward understanding of the molecular basis of primary open angle glaucoma (POAG) and steroid-induced secondary OAG, we quantified proteomic changes in trabecular meshwork (TM) cells following treatment with transforming growth factor β2 (TGF-β2) or dexamethasone (Dex).
Primary cultures of TM cells from four human donors were treated with TGF-β2 or with Dex and analyzed by LC MS/MS iTRAQ technology. Protein quantitation required ≥ 2 unique peptides per protein and utilized code written in R. Proteins present in ≥ 3 cell samples and exhibiting average protein ratios above or below the mean by at least 1 SD and p values < 0.06 were considered of higher or lower abundance.
Several mitochondrial proteins were significantly changed in TM cells by either TGF-β2 or Dex, including one elevated and 7 reduced by TGF-β2 and 6 elevated and 2 reduced by Dex. Six mitochondrial proteins were potentially altered by both treatments, including superoxide dismutase 2 and sulfide:quinone oxidoreductase. Four other proteins were significantly altered by both treatments, including paladin and prolyl 4-hydroxylase α1 and α2.
Mitochondrial proteomic changes induced by TGF-β2 or Dex implicate mitochondrial dysfunction in TM cells as a contributing factor to TM senescence and/or oxidative damage in the aqueous humor outflow pathway leading to elevated intraocular pressure in POAG. Other proteomic changes support ECM remodeling and disrupted cytoskeletal and cell-cell interactions in glaucoma pathology. Common physiological consequences of TGF-β2- and Dex-treatments may account in part for increased risk of OAG in steroid responders.
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