Inhibition of ERK1/2 and Activation of LXR Synergistically Reduce Atherosclerotic Lesions in ApoE-Deficient Mice
Inhibition of ERK1/2 and Activation of LXR Synergistically Reduce Atherosclerotic Lesions in ApoE-Deficient Mice
复制标题
抑制 ERK1/2 和激活 LXR 可协同减少 ApoE 缺陷小鼠的动脉粥样硬化病变。
DOI：
10.1161/atvbaha.114.305116
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发表时间：
2015-04-01
影响因子：
8.7
通讯作者：
Han, Jihong
中科院分区：
文献类型：
--
作者：
Chen, Yuanli;Duan, Yajun;Han, Jihong
肝脏X受体（LXR）的激活抑制动脉粥样硬化，但诱导高脂血症。体外研究表明，丝裂原活化蛋白激酶激酶1/2（MEK 1/2）抑制剂可协同LXR配体诱导的巨噬细胞ABCA 1表达和胆固醇流出。在这项研究中，我们确定了MEK 1/2（U 0126）和LXR配体（T0901317）是否可以在减少动脉粥样硬化方面具有协同作用，同时消除LXR配体诱导的脂肪肝和高甘油三酯血症。我们还着手确定action.Approach和Results-Wild-type小鼠的细胞机制，以确定U 0126对高脂饮食或高脂饮食加T0901317诱导的短暂血脂异常和肝损伤的影响。使用ApoE缺陷（apoE（-/-））小鼠或具有晚期病变的小鼠来确定T0901317和U 0126的组合对动脉粥样硬化和高脂血症的作用。我们发现，U 0126保护动物免受T0901317诱导的短暂或长期肝脂质蓄积、肝损伤和高胆固醇血症。同时，T0901317和U 0126的组合以协同方式抑制动脉粥样硬化的发展，并减少晚期病变。机制上，除了协同诱导巨噬细胞ABCA 1表达外，U 0126和T0901317的组合维持动脉壁完整性，抑制巨噬细胞在动脉中的积聚和巨噬细胞/泡沫细胞的形成，并激活胆固醇的逆向转运。抑制T0901317诱导的脂质积累的组合U 0126可能是由于失活的脂肪生成和激活的脂解/脂肪酸氧化pathways.Conclusions-Our研究表明，丝裂原活化蛋白激酶激酶1/2抑制剂和LXR配体的组合可以作为一种新的疗法，协同减少动脉粥样硬化，同时消除LXR诱导的有害影响。
Objective-Activation of liver X receptor (LXR) inhibits atherosclerosis but induces hypertriglyceridemia. In vitro, it has been shown that mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor synergizes LXR ligand-induced macrophage ABCA1 expression and cholesterol efflux. In this study, we determined whether MEK1/2 (U0126) and LXR ligand (T0901317) can have a synergistic effect on the reduction of atherosclerosis while eliminating LXR ligand-induced fatty livers and hypertriglyceridemia. We also set out to identify the cellular mechanisms of the actions.Approach and Results-Wild-type mice were used to determine the effect of U0126 on a high-fat diet or high-fat diet plus T0901317-induced transient dyslipidemia and liver injury. ApoE deficient (apoE(-/-)) mice or mice with advanced lesions were used to determine the effect of the combination of T0901317 and U0126 on atherosclerosis and hypertriglyceridemia. We found that U0126 protected animals against T0901317-induced transient or long-term hepatic lipid accumulation, liver injury, and hypertriglyceridemia. Meanwhile, the combination of T0901317 and U0126 inhibited the development of atherosclerosis in a synergistic manner and reduced advanced lesions. Mechanistically, in addition to synergistic induction of macrophage ABCA1 expression, the combination of U0126 and T0901317 maintained arterial wall integrity, inhibited macrophage accumulation in aortas and formation of macrophages/foam cells, and activated reverse cholesterol transport. The inhibition of T0901317-induced lipid accumulation by the combined U0126 might be attributed to inactivation of lipogenesis and activation of lipolysis/fatty acid oxidation pathways.Conclusions-Our study suggests that the combination of mitogen-activated protein kinase kinase 1/2 inhibitor and LXR ligand can function as a novel therapy to synergistically reduce atherosclerosis while eliminating LXR-induced deleterious effects.