Atmospheric fine particulate matter exposure exacerbates atherosclerosis in apolipoprotein E knockout mice by inhibiting autophagy in macrophages via the PI3K/Akt/mTOR signaling pathway.
Atmospheric fine particulate matter exposure exacerbates atherosclerosis in apolipoprotein E knockout mice by inhibiting autophagy in macrophages via the PI3K/Akt/mTOR signaling pathway.
复制标题
大气细颗粒物暴露通过PI3K/Akt/mTOR信号通路抑制巨噬细胞自噬加剧载脂蛋白E基因敲除小鼠动脉粥样硬化
DOI：
10.1016/j.ecoenv.2020.111440
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发表时间：
2020-10
影响因子：
6.8
通讯作者：
Qiang Wan;Ming Yang;Zhongyong Liu;Jianguang Wu
中科院分区：
文献类型：
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作者：
Qiang Wan;Ming Yang;Zhongyong Liu;Jianguang Wu
细颗粒物（PM2.5）暴露与动脉粥样硬化密切相关。缺陷性巨噬细胞自噬在晚期动脉粥样硬化中起加速作用，然而，巨噬细胞自噬是否与PM2.5诱导的动脉粥样硬化的发展有关尚未完全详细分析。本研究旨在探讨巨噬细胞自噬与PM2.5诱导的动脉粥样硬化之间的关系及其机制。将ApoE-/-小鼠随机暴露于PM2. 5或过滤空气中3个月，分离巨噬细胞RAW 264. 7，用PM2. 5刺激巨噬细胞RAW 264. 7，分别用PI 3 K/Akt/mTOR通路选择性抑制剂LY 294002、曲西立宾和雷帕霉素进行体内外实验，探讨其可能的作用机制。我们发现，PM2.5可显著加速ApoE−/−小鼠动脉粥样硬化斑块形成，升高血清TC和LDL-C水平，加速RAW264.7细胞脂质蓄积，升高血清和上清液中IL-6、TNF-α和hs-CRP水平，减少主动脉斑块和RAW264.7细胞中自噬体的数量，降低自噬相关基因LC 3-I的表达，LC 3-II和Beclin 1在主动脉组织和RAW 264. 7细胞中的表达增加，而在主动脉组织和RAW 264. 7细胞中自噬调节因子p62的表达增加，PI 3 K、Akt和mTOR的分布增加，p-PI 3 K、p-Akt和p-mTOR蛋白的表达增加。然而，PM2.5的这些作用随着LY 294002、曲西立滨或雷帕霉素的施用而加重。本研究表明，PI 3 K/Akt/mTOR信号通路参与了PM2. 5诱导的巨噬细胞自噬的抑制作用，PM2. 5通过激活PI 3 K/Akt/mTOR信号通路下调巨噬细胞自噬，加速动脉粥样硬化的发生。
Fine particulate matter (PM2.5) exposure is intimately linked to atherosclerosis. Defective macrophages autophagy plays an accelerated role in advanced atherosclerosis, however, whether macrophages autophagy has been implicated in the development of PM2.5-induced atherosclerosis has not been analyzed in full detail. Here we aimed to investigate the association between macrophages autophagy and PM2.5-induced atherosclerosis, as well as the underlying mechanisms. ApoE–/–mice were randomly exposed to PM2.5or filtered air for 3 months, macrophage RAW264.7 cells were isolated and were stimulated with PM2.5sample, selective inhibitors of PI3K/Akt/mTOR pathway LY294002, triciribine, and rapamycin were used in vitro and in vivo to detect the potential mechanisms. We found that PM2.5could significantly accelerate atherosclerotic plaque formation in ApoE−/−mice, increase serum levels of TC and LDL-C, accelerate lipid accumulation in RAW264.7 cells, elevate serum and supernatant levels of IL-6, TNF-α and hs-CRP, decrease the number of autophagosomes in aortic plaque and RAW264.7 cells, reduce the expressions of autophagy-related genes LC3-I, LC3-II and Beclin1 in aortic tissues and RAW264.7 cells but increase the expression of autophagy regulator p62, elevate PI3K, Akt and mTOR distributions in aorta, and increase p-PI3K, p-Akt and p-mTOR protein expressions in aorta and RAW264.7 cells. However, these effects of PM2.5were aggravated with the administration of LY294002, triciribine, or rapamycin. This study indicated that the PI3K/Akt/mTOR pathway is involved in the suppression of autophagy induced by PM2.5in macrophages, the accelerated effect of PM2.5on atherosclerosis was mediated by down-regulation of macrophages autophagy via activating the PI3K/Akt/mTOR signaling pathway.