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Olya Pokrovskaya, Deborah Wallace, Colm J O'Brien; Statins modify the fibrotic response of human trabecular meshwork and lamina cribrosa cells to mechanical stretch.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3545.
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Epidemiological studies suggest that patients who take 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, commonly known as statins, have a lower risk of developing glaucoma, and lower rates of glaucoma progression. Statins have been shown to have anti-inflammatory, anti-fibrotic, and immunomodulatory actions and hence may well represent a new therapeutic avenue in glaucoma. Cells of the trabecular meshwork (TM) and lamina cribrosa (LC) are subjected to various mechanical and biological stresses in the setting of glaucoma. This can result in altered gene expression, reorganisation of the actin cytoskeleton, and ultimately tissue stiffening, thus contributing to glaucoma progression. Previous work by Song et al (IOVS, 2005) has shown that porcine TM cells treated with lovastatin exhibit changes in cell shape and cytoskeletal arrangement. The objective of this study is to investigate how statins affect the cytoskeleton of human TM and LC cells, and how this may alter the fibrotic response of these cells to mechanical stress.
Primary human trabecular meshwork (TM) and lamina cribrosa (LC) cells from age-matched (p > 0.05) normal and glaucoma donors were cultured. Rhodamine-phalloidin staining was used to examine the actin cytoskeleton. Normal and glaucomatous TM cells were then subjected to 15% cyclical mechanical stretch (CMS), in the presence or absence of pretreatment with lovastatin (15-30µM). Protein expression of fibrotic genes (TGF-β, α-SMA) was analysed using Western Blot.
Treatment of human TM and LC cells in culture with lovastatin (15-30µM) resulted in disruption of the actin cytoskeleton. CMS (15%, 1Hz, for 12-24 hours) caused reorganisation of the cytoskeleton to form dense stress fibres (as shown by Rhodamine-phalloidin staining), and increased expression of fibrotic genes (as shown by Western blot). Pretreatment of TM cells with lovastatin followed by CMS resulted in reduced fibrotic gene expression, and profound disruption of the cytoskeleton.
Little is known regarding the effect of statins on ocular tissues at a cellular level. Our findings provide new insight into the possible mechanism of action of statins in glaucoma through reorganisation of the actin cytoskeleton and altered expression of fibrotic genes including TGFβ and α-SMA.
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