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R. Sui, N. Gordiyenko, N. Strunnikova, C. Zhi, I. MacDonald; Simvastatin Affects Viability, Morphology and Phagocytosis of Human Cells in Culture. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3406.
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Dermal fibroblasts were cultured from CHM patients and age-matched controls. Human fetal RPE cells were transfected with non-targeting and Rep1 siRNA. Cell proliferation and viability were evaluated by mitochondrial dehydrogenase activity. Morphological changes were examined by phase-contrast microscopy. Actin reorganization was observed by immunocytochemistry and confocal microscopy. Phagocytosis was induced in human fetal RPE cells with bovine photoreceptor outer segments (POS) and quantified. The prenylation of small G-proteins was assessed comparing their distribution between cell membrane fractions (prenylated) and cytosolic fractions (unprenylated).
Fibroblasts and hfRPE cells treated with statin showed decreased proliferation in a dose- and time-dependent pattern. Phagocytosis of POS was reduced when hfRPE cells were incubated with simvastatin. Phagocytosis by hfRPE cells after Rep1 knock down was significantly reduced by simvastatin. Similarly, simvastatin induced actin rearrangement and reduced cell viability more dramatically in. CHM fibroblasts (lacking Rep-1) and hfRPE cells after Rep1 knock down. Less Rab and Rac proteins were expressed in cytosolic fractions after treatment with simvastatin.
Statin inhibited cell proliferation, disrupted the cytoskeleton, and decreased hfRPE phagocytosis. These effects were independent of cholesterol reduction but due to insufficient isoprenylation of small G-proteins. Alternates to statin therapy could be considered for CHM patients with pre-existing deficient isoprenylation.
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