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TSPO 配体促进脉络膜内皮细胞胆固醇外流，抑制氧化应激和炎症。

TSPO Ligands Promote Cholesterol Efflux and Suppress Oxidative Stress and Inflammation in Choroidal Endothelial Cells.

机构信息

Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK.

Department of Vision Science, Glasgow Caledonian University, Glasgow G4 0BA, UK.

出版信息

Int J Mol Sci. 2018 Nov 24;19(12):3740. doi: 10.3390/ijms19123740.

DOI:10.3390/ijms19123740
PMID:30477223
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6321017/
Abstract

Choroidal endothelial cells supply oxygen and nutrients to retinal pigment epithelial (RPE) cells and photoreceptors, recycle metabolites, and dispose of metabolic waste through the choroidal blood circulation. Death of the endothelial cells of the choroid may cause abnormal deposits including unesterified and esterified cholesterol beneath RPE cells and within Bruch's membrane that contribute to the progression of age-related macular degeneration (AMD), the most prevalent cause of blindness in older people. Translocator protein (TSPO) is a cholesterol-binding protein that is involved in mitochondrial cholesterol transport and other cellular functions. We have investigated the role of TSPO in choroidal endothelial cells. Immunocytochemistry showed that TSPO was localized to the mitochondria of choroidal endothelial cells. Choroidal endothelial cells exposed to TSPO ligands (Etifoxine or XBD-173) had significantly increased cholesterol efflux, higher expression of cholesterol homeostasis genes (, , , and ), and reduced biosynthesis of cholesterol and phospholipids from [C]acetate, when compared to untreated controls. Treatment with TSPO ligands also resulted in reduced production of reactive oxygen species (ROS), increased antioxidant capacity, and reduced release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and VEGF) induced by oxidized LDL. These data suggest TSPO ligands may offer promise for the treatment of AMD.

摘要

脉络膜内皮细胞为视网膜色素上皮 (RPE) 细胞和光感受器提供氧气和营养物质，通过脉络膜血液循环回收代谢物，并处理代谢废物。脉络膜内皮细胞的死亡可能导致异常沉积物的形成，包括 RPE 细胞下方和 Bruch 膜内未酯化和酯化胆固醇，这些沉积物是导致年龄相关性黄斑变性 (AMD) 的原因，AMD 是老年人失明的最常见原因。转位蛋白 (TSPO) 是一种胆固醇结合蛋白，参与线粒体胆固醇转运和其他细胞功能。我们研究了 TSPO 在脉络膜内皮细胞中的作用。免疫细胞化学显示 TSPO 定位于脉络膜内皮细胞的线粒体。与未处理的对照组相比，暴露于 TSPO 配体 (Etifoxine 或 XBD-173) 的脉络膜内皮细胞胆固醇外排明显增加，胆固醇稳态基因 (、、、和) 的表达更高，并且从 [C]乙酸合成胆固醇和磷脂的生物合成减少。TSPO 配体的治疗还导致活性氧 (ROS) 的产生减少、抗氧化能力增加和由氧化 LDL 诱导的促炎细胞因子 (IL-1β、IL-6、TNF-α 和 VEGF) 的释放减少。这些数据表明 TSPO 配体可能为 AMD 的治疗提供希望。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/881f/6321017/5c5e07825850/ijms-19-03740-g006.jpg
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