靶向 HDAC6 通过 NF-κB/NLRP3 通路减弱尼古丁诱导的巨噬细胞焦亡,Atherosclerosis

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靶向 HDAC6 通过 NF-κB/NLRP3 通路减弱尼古丁诱导的巨噬细胞焦亡
Atherosclerosis ( IF 4.9 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.atherosclerosis.2020.11.021
Shuang Xu ₁ , Hangwei Chen ₂ , Huaner Ni ₂ , Qiuyan Dai ₂

Affiliation

背景和目的在动脉粥样硬化的发展过程中，尼古丁会激活巨噬细胞炎症。然而，尼古丁是否诱导巨噬细胞焦亡及其潜在机制尚不清楚。本研究旨在研究组蛋白去乙酰化酶 6 (HDAC6) 在尼古丁诱导的巨噬细胞焦亡中的作用。方法在体内研究中，尼古丁被给予 8 周龄的 ApoE-/- 小鼠，并喂食高脂肪饮食 (HFD) 12 周。TUNEL/CD68 和 Caspase-1/CD68 染色用于评估斑块中的巨噬细胞焦亡。对于体外研究，使用蛋白质印迹、乳酸脱氢酶活性 (LDH)、共免疫沉淀、染色质免疫沉淀和免疫荧光来评估 RAW264.7 细胞中的细胞焦亡和相关信号通路。结果高脂肪饮食和尼古丁上调了动脉粥样硬化病变中的巨噬细胞焦亡。尼古丁促进 RAW264.7 细胞的细胞焦亡，这可以通过裂解的 Caspase1、NLRP3、IL-1β、IL-18 的表达增加和 LDH 释放增加来证明。HDAC6 的抑制抑制了尼古丁诱导的细胞焦亡，这部分是由 p65 乙酰化和 NLRP3 转录介导的。沉默 p65 或 NLRP3 导致 RAW264.7 细胞的焦亡减少。结论尼古丁通过 HDAC6/NF-κB/NLRP3 信号通路诱导动脉粥样硬化中的巨噬细胞焦亡。这部分由 p65 乙酰化和 NLRP3 转录介导。沉默 p65 或 NLRP3 导致 RAW264.7 细胞的焦亡减少。结论尼古丁通过 HDAC6/NF-κB/NLRP3 信号通路诱导动脉粥样硬化中的巨噬细胞焦亡。这部分由 p65 乙酰化和 NLRP3 转录介导。沉默 p65 或 NLRP3 导致 RAW264.7 细胞的焦亡减少。结论尼古丁通过 HDAC6/NF-κB/NLRP3 信号通路诱导动脉粥样硬化中的巨噬细胞焦亡。

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Targeting HDAC6 attenuates nicotine-induced macrophage pyroptosis via NF-κB/NLRP3 pathway

BACKGROUND AND AIMS During the development of atherosclerosis, nicotine activates macrophage inflammation. However, whether nicotine induces macrophage pyroptosis and the underlying mechanisms remain unclear. This study aimed to investigate the role of histone deacetylase 6 (HDAC6) in nicotine-induced macrophage pyroptosis. METHODS For the in vivo study, nicotine was administered to 8-week-old ApoE-/- mice fed a high-fat diet (HFD) for 12 weeks. TUNEL/CD68 and Caspase-1/CD68 staining was used to assess macrophage pyroptosis in plaque. For the in vitro study, Western blotting, lactic dehydrogenase activity (LDH), coimmunoprecipitation, chromatin immunoprecipitation and immunofluorescence were used to evaluate pyroptosis and related signaling pathway in RAW264.7 cells. RESULTS A high-fat diet and nicotine upregulated macrophage pyroptosis in atherosclerotic lesions. Nicotine promoted pyroptosis in RAW264.7 cells, as evidenced by increased expression of cleaved Caspase1, NLRP3, IL-1β, IL-18, and elevated LDH release. Inhibition of HDAC6 suppressed nicotine-induced pyroptosis, which is partly mediated by p65 acetylation and NLRP3 transcription. Silencing p65 or NLRP3 resulted in decreased pyroptosis in RAW264.7 cells. CONCLUSIONS Nicotine induces macrophage pyroptosis in atherosclerosis through HDAC6/NF-κB/NLRP3 signaling pathway.

更新日期：2021-01-01

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