%0 Journal Article %A Shaolan Wang %A Xinya Xie %A Ting Lei %A Kang Zhang %A Baochang Lai %A Zihui Zhang %A Youfei Guan %A Guangmei Mao %A Lei Xiao %A Nanping Wang %T Statins Attenuate Activation of the NLRP3 Inflammasome by Oxidized-LDL or TNF-α in Vascular Endothelial Cells through a PXR-dependent mechanism %D 2017 %R 10.1124/mol.116.108100 %J Molecular Pharmacology %P mol.116.108100 %X 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 qRT-PCR showed that oxidized-LDL (oxLDL) or tumor necrosis factor alpha (TNFα) activated the NLRP3 inflammasome in ECs. Simvastatin or mevastatin significantly suppressed the effects of oxLDL or TNFα. Promoter reporter assays and siRNA knockdown revealed that statins inhibit oxLDL-mediated NLRP3 inflammasome activation via the pregnane X receptor (PXR). In addition, PXR agonists (rifampicin and SR12813) or overexpression of a constitutively active PXR (VP-PXR) markedly suppressed the NLRP3 inflammasome activation. Conversely, PXR knockdown abrogated the suppressive effect of rifampicin on NLRP3 inflammasome activation. Knockdown of lectin-like oxidized LDL receptor (LOX-1) or overexpression of IκBα attenuated oxLDL- or TNFα-triggered activation of the NLRP3 inflammasome. Chromatin immunoprecipitation assays indicated that mevastatin inhibited NF-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 oxLDL and TNFα in ECs, providing a new mechanism for the cardiovascular benefit of statins. %U https://molpharm.aspetjournals.org/content/molpharm/early/2017/05/25/mol.116.108100.full.pdf