Epidemiological evidence indicates that selenium supplementation may increase risk for ocular hypertension and glaucoma. The purpose of this project was to determine the effects of selenium on the conventional "trabecular" aqueous outflow pathway, a likely site of pathology for glaucoma. Human trabecular meshwork (HTM) cells and human umbilical vein endothelial cells (HUVECs) were treated with selenium (MSeA) at or near physiologically relevant concentrations. Selenium uptake by cells was monitored using mass spectrometry. While detectible changes in intracellular selenium were observed after exposure to 1-10 uM MSeA for 24 hours, the majority remained in the conditioned medium. The high concentrations of extracellular selenium we observed raised the possibility that selenium has an extracellular target.To investigate the role of selenium in extracellular matrix turnover, I examined alterations in protein secretion and intracellular signaling. MSeA treatment (5-10 uM) led to a significant decrease in the secretion of matrix metalloproteinase -2 and its inhibitor after 6-24 hours and to a dose-dependent decrease in kinase signaling. Later, I investigated the possibility that integrins are an extracellular target of selenium by monitoring morphological changes in HTM cells and by treating them with divalent cations. MSeA stimulated morphological changes consistent with a decrease in integrin function. These occurred before (less than 3 hours) alterations in protein secretion and intracellular signaling (3-6 hours). Zinc treatment prevented MSeA-mediated alterations in protein secretion and changes in cell-matrix adhesion.Finally markers of HTM cell homeostasis were examined. MSeA treatment (5 uM) led to a 60% decrease in protein synthesis after 3 hours and a 60% reduction in protein secretion, without causing significant alterations in cell viability and total ATP. To assess the physiological relevance of my results, anterior segments were perfused with MSeA to determine its effects on aqueous outflow facility. Preliminary results suggest that MSeA leads to a decrease in outflow facility.The combination of MSeA-induced decreases in several indicators of HTM cell homeostasis (without adversely effects on cell viability at physiologically relevant doses) and decreases in outflow facility provide a possible mechanism for selenium-associated ocular hypertension.

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