Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility.
Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility.
复制标题
甾醇调节元件结合蛋白2激活内皮细胞NLRP3炎症小体介导血流动力学诱导的动脉粥样硬化易感性
DOI：
10.1161/circulationaha.113.002714
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发表时间：
2013-08-06
期刊：
影响因子：
37.8
通讯作者：
Shyy JY
中科院分区：
文献类型：
--
作者：
Xiao H;Lu M;Lin TY;Chen Z;Chen G;Wang WC;Marin T;Shentu TP;Wen L;Gongol B;Sun W;Liang X;Chen J;Huang HD;Pedra JH;Johnson DA;Shyy JY
动脉粥样硬化病变局灶性的分子基础尚不清楚。在这里，我们探讨了扰动的流动模式是否会激活先天免疫反应，通过甾醇调节元件结合蛋白 2 (SREBP2) 在血管内皮细胞 (EC) 中形成 NLRP3 炎症小体支架。振荡流激活 SREBP2 并诱导 EC 中的 NLRP3 炎性体。潜在机制涉及 SREBP2 反式激活 NADPH 氧化酶 2 (NOX2) 和 NLRP3。一致地，在小鼠主动脉的动脉粥样硬化易发区域，SREBP2、NOX2 和 NLRP3 水平升高，表明 SREBP2 激活的 NLRP3 炎症小体导致内皮功能紊乱，炎症加剧。模仿动脉粥样硬化血流的效应，SREBP2 激活形式的 EC 特异性过度表达与高脂血症协同作用，增加小鼠主动脉抗动脉粥样硬化区域的动脉粥样硬化。动脉粥样硬化流通过 SREBP2 激活诱导内皮细胞中的 NLRP3 炎性小体。内皮细胞先天免疫力的增加与高脂血症协同作用，导致动脉粥样硬化病变的地形分布。
The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells (ECs) via sterol regulatory element binding protein 2 (SREBP2). Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in ECs. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 (NOX2) and NLRP3. Consistently, SREBP2, NOX2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, EC-specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas. Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographic distribution of atherosclerotic lesions.