Abstract
BackgroundCurrent guidelines encourage the use of statins to reduce the risk of cardiovascular disease in diabetic patients; however the impact of these drugs on diabetic retinopathy is not well defined. Moreover, pleiotropic effects of statins on the highly specialised retinal microvascular endothelium remain largely unknown. The objective of this study was to investigate the effects of clinically relevant concentrations of simvastatin on retinal endothelium in vitro and in vivo.Methods and FindingsRetinal microvascular endothelial cells (RMECs) were treated with 0.01–10 µM simvastatin and a biphasic dose-related response was observed. Low concentrations enhanced microvascular repair with 0.1 µM simvastatin significantly increasing proliferation (p<0.05), and 0.01 µM simvastatin significantly promoting migration (p<0.05), sprouting (p<0.001), and tubulogenesis (p<0.001). High concentration of simvastatin (10 µM) had the opposite effect, significantly inhibiting proliferation (p<0.01), migration (p<0.01), sprouting (p<0.001), and tubulogenesis (p<0.05). Furthermore, simvastatin concentrations higher than 1 µM induced cell death. The mouse model of oxygen-induced retinopathy was used to investigate the possible effects of simvastatin treatment on ischaemic retinopathy. Low dose simvastatin(0.2 mg/Kg) promoted retinal microvascular repair in response to ischaemia by promoting intra-retinal re-vascularisation (p<0.01). By contrast, high dose simvastatin(20 mg/Kg) significantly prevented re-vascularisation (p<0.01) and concomitantly increased pathological neovascularisation (p<0.01). We also demonstrated that the pro-vascular repair mechanism of simvastatin involves VEGF stimulation, Akt phosphorylation, and nitric oxide production; and the anti-vascular repair mechanism is driven by marked intracellular cholesterol depletion and related disorganisation of key intracellular structures.ConclusionsA beneficial effect of low-dose simvastatin on ischaemic retinopathy is linked to angiogenic repair reducing ischaemia, thereby preventing pathological neovascularisation. High-dose simvastatin may be harmful by inhibiting reparative processes and inducing premature death of retinal microvascular endothelium which increases ischaemia-induced neovascular pathology. Statin dosage should be judiciously monitored in patients who are diabetic or are at risk of developing other forms of proliferative retinopathy.
Highlights
Statins are potent and effective inhibitors of cholesterol biosynthesis that are widely used to treat hypercholesterolemia
High-dose simvastatin may be harmful by inhibiting reparative processes and inducing premature death of retinal microvascular endothelium which increases ischaemiainduced neovascular pathology
The percentage of BrdU-positive cells decreased in a dosedependent manner (Figure 1C). 0.1 mM simvastatin significantly increased the number of BrdU-positive cells which was akin to the vascular endothelial growth factor (VEGF)-induced response (Figure 1B) while 5 and 10 mM simvastatin significantly decreased the number of BrdU-positive cells (Figure 1B)
Summary
Statins are potent and effective inhibitors of cholesterol biosynthesis that are widely used to treat hypercholesterolemia. Beyond this well-defined mode of action for statins, several clinical trials such as 4S [1], WOSCOPS [2], CARE [3], and HPS [4] have demonstrated that this class of drugs can protect against cardiovascular disease (CVD) through an additional mechanism that is independent of cholesterol lowering [5]. Current guidelines encourage the use of statins to reduce the risk of cardiovascular disease in diabetic patients; the impact of these drugs on diabetic retinopathy is not well defined. Pleiotropic effects of statins on the highly specialised retinal microvascular endothelium remain largely unknown. The objective of this study was to investigate the effects of clinically relevant concentrations of simvastatin on retinal endothelium in vitro and in vivo
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