Chitinase Inhibition Promotes Atherosclerosis in Hyperlipidemic Mice
Chitinase Inhibition Promotes Atherosclerosis in Hyperlipidemic Mice
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DOI：
10.1016/j.ajpath.2013.04.003
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发表时间：
2013-07-01
影响因子：
6
通讯作者：
Boisvert, William A.
中科院分区：
文献类型：
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作者：
Kitamoto, Shiro;Egashira, Kensuke;Boisvert, William A.
几丁质酶1（CHIT 1）由活化的巨噬细胞分泌。几丁质酶活性在动脉粥样硬化患者血清中升高，并存在于动脉粥样硬化斑块中。然而，CHIT 1在动脉粥样硬化中的作用尚不清楚。食蟹猴动脉粥样硬化的初步研究显示CHIT 1与巨噬细胞浸润区域密切相关。因此，我们研究了几丁质酶抑制剂，allosamidin，对巨噬细胞功能在体外和动脉粥样硬化的发展在体内的影响。在RAW264.7细胞中，allosamidin升高单核细胞趋化蛋白1和肿瘤坏死因子α的表达，并增加激活蛋白1和核因子-κ B转录活性。虽然诱导型一氧化氮合酶，IL-6和IL-1 β的表达增加，Arg1的表达减少几丁质酶抑制，表明抑制CHIT1活性极化成M1表型的巨噬细胞。Allosamidin降低清道夫受体AI、CD36、ABCA 1和ABCG 1的表达，从而抑制巨噬细胞中胆固醇摄取和载脂蛋白AI介导的胆固醇流出。这些作用在原代巨噬细胞中用CHIT1 siRNA转染和CHIT1质粒转染实验证实。载脂蛋白E缺乏的高脂血症小鼠用阿洛酰胺持续给药6周并喂食致动脉粥样硬化饮食，显示动脉粥样硬化病变形成加重。这些数据表明，CHIT 1发挥保护作用，通过抑制炎症反应和极化巨噬细胞向M2表型，并促进脂质摄取和胆固醇流出巨噬细胞动脉粥样硬化。
Chitinase 1 (CHIT1) is secreted by activated macrophages. Chitinase activity is raised in atherosclerotic patient sera and is present in atherosclerotic plaque. However, the role of CHIT1 in atherosclerosis is unknown. Preliminary studies of atherosclerosis in cynomolgous monkeys revealed CHIT1 to be closely correlated with areas of macrophage infiltration. Thus, we investigated the effects of a chitinase inhibitor, allosamidin, on macrophage function in vitro and on atherosclerotic development in vivo. In RAW264.7 cells, allosamidin elevated monocyte chemoattractant protein 1 and tumor necrosis factor alpha expression, and increased activator protein 1 and nuclear factor-kappa B transcriptional activity. Although inducible nitric oxide synthase, IL-6, and IL-1 beta expression were increased, Arg1 expression was decreased by chitinase inhibition, suggesting that suppression of CHIT1 activity polarizes macrophages into a M1 phenotype. Allosamidin decreased scavenger receptor AI, CD36, ABCA1, and ABCG1 expression which Led to suppression of cholesterol uptake and apolipoprotein AI-mediated cholesterol efflux in macrophages. These effects were confirmed with CHIT1 siRNA transfection and CHIT1 plasmid transfection experiments in primary macrophages. Apolipoprotein E-deficient hyperlipidemic mice treated for 6 weeks with constant administration of allosamidin and fed an atherogenic diet showed aggravated atherosclerotic Lesion formation. These data suggest that CHIT1 exerts protective effects against atherosclerosis by suppressing inflammatory responses and polarizing macrophages toward an M2 phenotype, and promoting lipid uptake and cholesterol efflux in macrophages.