Wei Xiao, Yang Ruomei, Wang Chengpan, Jian Xun, Li Ling, Liu Hua, Yang Gangyi, Li Zhiyong
Department of Endocrinology, Yongchuan Hospital, Chongqing Medical University, 402160, Chongqing, China.
Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, 400010, Chongqing, China.
Cardiovasc Pathol. 2017 Mar-Apr;27:1-8. doi: 10.1016/j.carpath.2016.11.003. Epub 2016 Nov 14.
Genome-wide association studies have shown that Krüppel-like factor 14 (KLF14) is associated with both Type 2 diabetes mellitus and lipid metabolism. However, its role in chronic inflammatory responses and the pathogenesis of atherosclerosis remains unknown. The present study was designed to investigate both in vivo and in vitro the impact of KLF14 on chronic inflammatory responses and atherosclerosis. ApoE KO mice, a well-established animal model of atherosclerosis, had higher expressions of KLF14 in aorta tissues than that in C57BL/6 J mice when fed the high-fat diet (HFD) or standard chow diet. Adenovirus-mediated KLF14 knockdown markedly reduced the circulating levels of proinflammatory cytokines and the formation of atherosclerotic lesions in HFD-fed ApoE KO mice. In the in vitro study, KLF14 overexpression in the RAW264.7 macrophages significantly increased the expressions of inflammatory cytokines, total cholesterol (TC), cholesteryl ester (CE), and the ratio of CE to TC in the cells treated with acetylated low-density lipoproteins (AcLDL). Conversely, KLF14 knockdown remarkably attenuated AcLDL-induced increase in TC, CE, and the ratio of CE to TC as well as the expressions of inflammatory cytokines. Furthermore, up-regulation or down-regulation of KLF14 markedly elevated or inhibited the phosphorylation levels of p38 MAPK and ERK1/2 in AcLDL-stimulated RAW264.7 macrophages, respectively. Importantly, treatment with p38 MAPK or ERK1/2 inhibitor nullified the effects of KLF14 on inflammatory cytokine expressions in the cells. These data demonstrate an important role for KLF14 expression in atherosclerotic lesion formation.
全基因组关联研究表明，Krüppel样因子14（KLF14）与2型糖尿病和脂质代谢均相关。然而，其在慢性炎症反应及动脉粥样硬化发病机制中的作用尚不清楚。本研究旨在在体内和体外研究KLF14对慢性炎症反应和动脉粥样硬化的影响。载脂蛋白E基因敲除（ApoE KO）小鼠是一种成熟的动脉粥样硬化动物模型，在喂食高脂饮食（HFD）或标准普通饮食时，其主动脉组织中KLF14的表达高于C57BL/6 J小鼠。腺病毒介导的KLF14敲低显著降低了喂食HFD的ApoE KO小鼠促炎细胞因子的循环水平和动脉粥样硬化病变的形成。在体外研究中，RAW264.7巨噬细胞中KLF14的过表达显著增加了用乙酰化低密度脂蛋白（AcLDL）处理的细胞中炎症细胞因子、总胆固醇（TC）、胆固醇酯（CE）以及CE与TC比值的表达。相反，KLF14敲低显著减弱了AcLDL诱导的TC、CE以及CE与TC比值的增加以及炎症细胞因子的表达。此外，KLF14的上调或下调分别显著提高或抑制了AcLDL刺激的RAW264.7巨噬细胞中p38丝裂原活化蛋白激酶（p38 MAPK）和细胞外信号调节激酶1/2（ERK1/2）的磷酸化水平。重要的是，用p38 MAPK或ERK1/2抑制剂处理消除了KLF14对细胞中炎症细胞因子表达的影响。这些数据证明了KLF14表达在动脉粥样硬化病变形成中的重要作用。
