SIRT1 inhibition promotes atherosclerosis through impaired autophagy.
SIRT1 inhibition promotes atherosclerosis through impaired autophagy.
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SIRT1 抑制通过受损的自噬促进动脉粥样硬化
DOI：
10.18632/oncotarget.17691
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Lin R
中科院分区：
文献类型：
--
作者：
Yang X;Wei J;He Y;Jing T;Li Y;Xiao Y;Wang B;Wang W;Zhang J;Lin R
SIRT1是一种高度保守的NAD+依赖性蛋白去乙酰化酶，在动脉粥样硬化(AS)的发病机制和治疗中起着关键作用。本研究的目的是研究SIRT1对ApoE-/-小鼠AS的潜在影响，以及OX-LDL刺激的人单核细胞系THP-1自噬的潜在机制。在体内，通过放置颈动脉环建立加速的小鼠动脉粥样硬化进展；然后，用SIRT1特异性抑制剂EX-527治疗小鼠4周。与对照组相比，EX-527处理组小鼠动脉粥样硬化病变面积明显增大。免疫染色方法证实，在斑块发生和发展过程中抑制SIRT1增强了斑块内巨噬细胞的渗透程度，并损害了自噬过程。利用体外培养的THP-1巨噬细胞暴露于ox-LDL，用不同的方法研究SIRT1功能、自噬通量、促炎细胞因子分泌和泡沫细胞形成之间的关系。结果表明，氧化低密度脂蛋白显著抑制SIRT1蛋白的表达和自噬水平，而促进MCP-1的产生和脂质摄取。此外，SIRT1抑制剂EX-527或SIRT1 siRNA的应用进一步减弱了ox-LDL诱导的自噬抑制。综上所述，我们的结果表明，抑制SIRT1通过增加MCP-1的表达和巨噬细胞的聚集，促进了ApoE-/-小鼠动脉粥样硬化斑块的发展。特别是，我们证明了阻断SIRT1可以加剧关键的自噬机制ATG5蛋白的乙酰化，ATG5蛋白进一步调节由ox-LDL触发的THP-1巨噬细胞衍生泡沫细胞的形成。
SIRT1, a highly conserved NAD+-dependent protein deacetylase, plays a pivotal role in the pathogenesis and therapy of atherosclerosis (AS). The aim of this study is to investigate the potential effects of SIRT1 on AS in ApoE–/– mice and the underlying mechanisms of autophagy in an ox-LDL-stimulated human monocyte cell line, THP-1. In vivo, the accelerated atherosclerotic progression of mice was established by carotid collar placement; then, mice were treated for 4 weeks with a SIRT1-specific inhibitor, EX-527. The atherosclerotic lesion size of EX-527-treated mice was greatly increased compared to that of the mice in the control group. Immunostaining protocols confirmed that the inhibition of SIRT1 during plaque initiation and progression enhanced the extent of intraplaque macrophage infiltration and impaired the autophagy process. In vitro cultured THP-1 macrophages exposed to ox-LDL were utilized to study the link between the SIRT1 function, autophagy flux, pro-inflammatory cytokine secretion, and foam cell formation using different methods. Our data showed that ox-LDL markedly suppressed SIRT1 protein expression and the autophagy level, while it elevated the MCP-1 production and lipid uptake. Additionally, the application of the SIRT1 inhibitor EX-527 or SIRT1 siRNA further attenuated ox-LDL-induced autophagy inhibition. In conclusion, our results show that the inhibition of SIRT1 promoted atherosclerotic plaque development in ApoE–/– mice by increasing the MCP-1 expression and macrophage accumulation. In particular, we demonstrate that blocking SIRT1 can exacerbate the acetylation of key autophagy machinery, the Atg5 protein, which further regulates the THP-1 macrophage-derived foam cell formation that is triggered by ox-LDL.
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影响因子：
19.6
作者：
Levine MH;Wang Z;Xiao H;Jiao J;Wang L;Bhatti TR;Hancock WW;Beier UH
通讯作者：
Beier UH
影响因子：
5.3
作者：
Burgmaier M;Schutters K;Willems B;van der Vorst EP;Kusters D;Chatrou M;Norling L;Biessen EA;Cleutjens J;Perretti M;Schurgers LJ;Reutelingsperger CP
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Reutelingsperger CP
影响因子：
5.4
作者：
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通讯作者：
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影响因子：
4.9
作者：
Picard, F;Guarente, L
通讯作者：
Guarente, L
影响因子：
5.2
作者：
Hung, Ching-Hsia;Chan, Shih-Hung;Tsai, Kun-Ling
通讯作者：
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