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R. J. Medina, C. O'Neill, T. A. Gardiner, A. W. Stitt; Simvastatin Modulates Retinal Endothelial Cell Function. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4459.
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© ARVO (1962-2015); The Authors (2016-present)
Statins are inhibitors of cholesterol biosynthesis that are widely used to treat patients with hypercholesterolemia. Recent studies have linked statins with several biologically diverse actions that go far beyond lowering cholesterol. These pleiotropic effects include reversing endothelial cell dysfunction. Interestingly, some reports have suggested that statins can influence the retinal circulation by inhibiting leukocyte accumulation in the retinas of diabetic rats. This indicates that statins could protect against diabetic retinopathy, however further experimental evidence is required before speculating on the potential clinical implications of these findings. Therefore the aim of this study was to investigate the effects of clinically relevant concentrations of Simvastatin, the most commonly prescribed statin, on retinal microvascular endothelial cell (RMEC) function.
RMECs were isolated from bovine retinas. The modulatory effects of Simvastatin were investigated within a range of assay systems that asses RMEC dysfunction relevant to diabetic retinopathy.Assays for quantifying RMEC proliferation, BrdU incorporation, migration, sprouting and tubulogenesis in Matrigel were performed. Concentration-dependent statin regulation of RMEC apoptosis was also investigated using TUNEL staining.
Modulation of RMEC function by Simvastatin was dependent on the concentration used. 0.01µM Simvastatin promoted cell migration (p<0.05) and sprouting (p<0.001) when compared to controls. These effects were comparable to VEGF treated cells and the statin response was blocked by co-treatment with L-NAME or Mevalonate. Simvastatin at 0.1µM and 1µM, both enhanced tubulogenesis (p<0.001). 0.1µM Simvastatin-treated cells showed higher rates of BrdU incorporation and population doublings, while concentrations higher than 1µM significantly inhibited cell proliferation, migration, sprouting, and tubulogenesis. High concentrations of Simvastatin also caused significant enhancement of TUNEL positive RMECs.
Simvastatin should not only be considered as a cholesterol lowering agent, but also as a potential modulator of retinal endothelial cell function in retinal capillaries. This study demonstrates that at low concentrations Simvastatin promotes angiogenesis and endothelial repair, while higher doses not only impair angiogenesis but induce endothelial cell death in the retinal microvasculature.
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