Endothelial ATP-binding cassette G1 in mouse endothelium protects against hemodynamic-induced atherosclerosis.
Endothelial ATP-binding cassette G1 in mouse endothelium protects against hemodynamic-induced atherosclerosis.
复制标题
DOI：
10.1016/j.bbrc.2016.06.050
复制
发表时间：
2016-08
影响因子：
3.1
通讯作者：
Shanshan Xue;Jiaxing Wang;Xu Zhang;Ying Shi;Bochuan Li;Qiankun Bao;W. Pang;Ding Ai;Yi Zhu;Jinlong He
中科院分区：
文献类型：
--
作者：
Shanshan Xue;Jiaxing Wang;Xu Zhang;Ying Shi;Bochuan Li;Qiankun Bao;W. Pang;Ding Ai;Yi Zhu;Jinlong He
持续性高脂血症下激活的血管内皮炎症是动脉粥样硬化形成的第一步。 ATP 结合盒 G1 (ABCG1) 是通过将胆固醇外流转运至高密度脂蛋白来维持甾醇和脂质稳态的关键因素。在本研究中，我们研究了 ABCG1 在小鼠早期动脉粥样硬化形成过程中内皮炎症激活中的保护作用及其潜在机制。生成内皮细胞 (EC) 特异性 ABCG1 转基因 (EC-ABCG1-Tg) 小鼠，并与低密度脂蛋白受体缺陷 (Ldlr−/−) 小鼠杂交。经过 4 周的西式饮食后，处死小鼠以评估动脉粥样硬化。用不同的流量处理人脐静脉内皮细胞，并通过腺病毒过表达 ABCG1 以研究体外机制。与Ldlr−/−小鼠主动脉相比，EC-ABCG1-Tg/Ldlr−/−主动脉显示早期病变减少。此外，EC-ABCG1-Tg/Ldlr−/−小鼠主动脉弓（而非胸主动脉）的病变区域显着减少，这表明 ABCG1 在动脉粥样硬化血流中具有保护作用。在体外，ABCG1 的过度表达减弱了振荡剪切应力引起的 EC 激活。 ABCG1 的过度表达会在体外减弱胆固醇激活的 ECs。在探索 ABCG1 减轻内皮炎症的机制时，我们发现 ABCG1 抑制内皮细胞中振荡流激活的核因子 kappa B 和 NLRP3 炎症小体。 ABCG1 可能通过抑制炎症反应来减少振荡剪切应力诱导的内皮激活，从而在早期动脉粥样硬化中发挥保护作用。
Activated vascular endothelium inflammation under persistent hyperlipidemia is the initial step of atherogenesis. ATP-binding cassette G1 (ABCG1) is a crucial factor maintaining sterol and lipid homeostasis by transporting cholesterol efflux to high-density lipoprotein. In this study, we investigated the protective effects of ABCG1 in endothelial inflammation activation during early-stage atherogenesis in mice and the underlying mechanisms. Endothelial cell (EC)-specific ABCG1 transgenic (EC-ABCG1-Tg) mice were generated and cross-bred with low-density lipoprotein receptor–deficient (Ldlr−/−) mice. After a 4-week Western-type diet, the mice were sacrificed for assessing atherosclerosis. Human umbilical vein ECs were treated with different flows, and ABCG1 was adenovirally overexpressed to investigate the mechanismin vitro. Compared withLdlr−/−mouse aortas, EC-ABCG1-Tg/Ldlr−/−aortas showed decreased early-stage lesions. Furthermore, the lesion area in the EC-ABCG1-Tg/Ldlr−/−mouse aortic arch but not thoracic aorta was significantly reduced, which suggests a protective role of ABCG1 under atheroprone flow.In vitro, overexpression of ABCG1 attenuated EC activation caused by oscillatory shear stress. Overexpression of ABCG1 blunted cholesterol-activated ECsin vitro. In exploring the mechanisms of ABCG1 attenuating endothelial inflammation, we found that ABCG1 inhibited oscillatory flow-activated nuclear factor kappa B and NLRP3 inflammasome in ECs. ABCG1 may play a protective role in early-stage atherosclerosis by reducing endothelial activation induced by oscillatory shear stress via suppressing the inflammatory response.