Previous work highlights the detrimental effect elevated retinal cholesterol levels have on diabetic retinopathy (DR) progression. We have shown that downregulation of LXRα/SIRT1 results in dysregulated cholesterol metabolism and increased retinal cholesterol levels. In turn, elevated cholesterol levels lead to the formation of retinal cholesterol crystals (CC), exacerbating the pro-inflammatory and apoptotic milieu present in the diabetic retina. The focus of this study was to investigate the therapeutic potential of cholesterol lowering drugs in preventing CC-induced retinal damage in endothelial cells and in a type 2 diabetic mouse model.
Methods : Human retinal endothelial cells (HREC) were treated with CC (2mg/ml) and/or CC pretreated with Atorvastatin (10mM), Rosuvastatin (10mM), or α cyclodextrin (10mM) for 24hrs. Inflammation was measured via IL6 and IL8 levels by qRTPCR. Cell survival was determined via trypan blue exclusion assay. Type 2 diabetes was modeled in vivo viathe db/db mouse model. Alpha cyclodextrin was administered three times a week for 2 weeks via subcutaneous injections (4g/kg). Cholesterol crystals were visualized using SEM and quantified using ImageJ software analysis.
Results : Pretreatment of CC with Atorvastatin, Rosuvastatin, or α cyclodextrin reduced the amount of crystals when compared to non-treated controls ex vivo. In culture, administration of CC significantly upregulated IL6 and IL8 expression
Sandra S Hammer; Delaney McFarland; George Abela; Sergio Li Calzi; Maria B Grant; Julia V Busik. Statins and α cyclodextrin treatments prevent cholesterol crystal-induced pathology in human retinal endothelial cells and in db/db mice. Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2928. ARVO Annual Meeting Abstract June 2021