他汀类药物通过一种依赖孕烷X受体（PXR）的机制减弱氧化型低密度脂蛋白（ox-LDL）或肿瘤坏死因子（TNF）对血管内皮细胞中NLRP3炎性小体的激活作用。
Statins Attenuate Activation of the NLRP3 Inflammasome by Oxidized LDL or TNF in Vascular Endothelial Cells through a PXR-Dependent Mechanism.
作者信息
Wang Shaolan, Xie Xinya, Lei Ting, Zhang Kang, Lai Baochang, Zhang Zihui, Guan Youfei, Mao Guangmei, Xiao Lei, Wang Nanping
机构信息
Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an , People's Republic of China (S.W., X.X., T.L., K.Z., B.L., Z.Z., L.X., N.W.); The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China (Y.G., N.W.); and Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio (G.M.).
Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an , People's Republic of China (S.W., X.X., T.L., K.Z., B.L., Z.Z., L.X., N.W.); The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China (Y.G., N.W.); and Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio (G.M.)
出版信息
Mol Pharmacol. 2017 Sep;92(3):256-264. doi: 10.1124/mol.116.108100. Epub 2017 May 25.
Excessive activation of the NLRP3 inflammasome is implicated in cardiovascular diseases. Statins exert an anti-inflammatory effect independent of their cholesterol-lowering effect. This study investigated the potential role of statins in the activation of the NLRP3 inflammasome in endothelial cells (ECs). Western blotting and quantitative reverse-transcription polymerase chain reaction showed that oxidized low-density lipoprotein (ox-LDL) or tumor necrosis factor α (TNF) activated the NLRP3 inflammasome in ECs. Simvastatin or mevastatin significantly suppressed the effects of ox-LDL or TNF Promoter reporter assays and small interfering RNA knockdown revealed that statins inhibit ox-LDL-mediated NLRP3 inflammasome activation via the pregnane X receptor (PXR). In addition, PXR agonists (rifampicin and SR12813) or overexpression of a constitutively active PXR markedly suppressed the NLRP3 inflammasome activation. Conversely, PXR knockdown abrogated the suppressive effect of rifampicin on NLRP3 inflammasome activation. Knockdown of lectin-like ox-LDL receptor or overexpression of IB-attenuated ox-LDL- or TNF-triggered activation of the NLRP3 inflammasome. Chromatin immunoprecipitation assays indicated that mevastatin inhibited nuclear factor-κB binding to the promoter regions of the human NLRP3 gene. Collectively, these results demonstrate that the statin activation of PXR inhibits the activation of NLRP3 inflammasome in response to atherogenic stimuli such as ox-LDL and TNF in ECs, providing a new mechanism for the cardiovascular benefit of statins.
NLRP3炎性小体的过度激活与心血管疾病有关。他汀类药物发挥抗炎作用，与其降低胆固醇的作用无关。本研究调查了他汀类药物在内皮细胞（ECs）中对NLRP3炎性小体激活的潜在作用。蛋白质印迹法和定量逆转录聚合酶链反应表明，氧化型低密度脂蛋白（ox-LDL）或肿瘤坏死因子α（TNF）可激活ECs中的NLRP3炎性小体。辛伐他汀或美伐他汀显著抑制ox-LDL或TNF的作用。启动子报告基因检测和小干扰RNA敲低显示，他汀类药物通过孕烷X受体（PXR）抑制ox-LDL介导的NLRP3炎性小体激活。此外，PXR激动剂（利福平与SR12813）或组成型活性PXR的过表达显著抑制了NLRP3炎性小体的激活。相反，PXR敲低消除了利福平对NLRP3炎性小体激活的抑制作用。凝集素样ox-LDL受体的敲低或IκB的过表达减弱了ox-LDL或TNF触发的NLRP3炎性小体激活。染色质免疫沉淀分析表明，美伐他汀抑制核因子κB与人NLRP3基因启动子区域的结合。总的来说，这些结果表明，他汀类药物激活PXR可抑制ECs中对致动脉粥样硬化刺激（如ox-LDL和TNF）产生反应的NLRP3炎性小体的激活，为他汀类药物对心血管有益作用提供了一种新机制。
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