Inhibition of ERK1/2 and Activation of LXR Synergistically Reduce Atherosclerotic Lesions in ApoE-Deficient Mice

被引：115

作者：

Chen, Yuanli ^{[1
,2
]}

Duan, Yajun ^{[1
,2
,3
]}

Yang, Xiaoxiao ^{[3
]}

Sun, Lei ^{[3
]}

Liu, Mengyang ^{[3
]}

Wang, Qixue ^{[3
]}

Ma, Xingzhe ^{[3
]}

Zhang, Wenwen ^{[3
]}

Li, Xiaoju ^{[3
]}

Hu, Wenquan ^{[4
]}

Miao, Robert Q. ^{[4
]}

Xiang, Rong ^{[2
]}

Hajjar, David P. ^{[5
]}

Han, Jihong ^{[1
,2
,3
]}

机构：

[1] Nankai Univ, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China

[2] Nankai Univ, Collaborat Innovat Ctr Biotherapy, Tianjin 300071, Peoples R China

[3] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China

[4] Med Coll Wisconsin, Dept Surg, Milwaukee, WI 53226 USA

[5] Cornell Univ, Dept Pathol, Weill Med Coll, New York, NY 10021 USA

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2015年 / 35卷 / 04期

基金：

美国国家科学基金会;

关键词：

atherosclerosis; extracellular signal-regulated map kinases; foam cells; hypertriglyceridemia; lipogenesis; liver X receptor; LIVER-X-RECEPTOR; REVERSE CHOLESTEROL TRANSPORT; CELL ACTIVATION; LIGAND; TRIGLYCERIDE; HOMEOSTASIS; EXPRESSION; ALPHA;

D O I：

10.1161/ATVBAHA.114.305116

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：948 / 959

页数：12

共 38 条

[31]

T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice [J].