Statins Attenuate Activation of the NLRP3 Inflammasome by Oxidized LDL or TNF α in Vascular Endothelial Cells through a PXR-Dependent Mechanism

Shaolan Wang; Xinya Xie; Ting Lei; Kang Zhang; Baochang Lai; Zihui Zhang; Youfei Guan; Guangmei Mao; Lei Xiao; Nanping Wang

doi:10.1124/mol.116.108100

Statins Attenuate Activation of the NLRP3 Inflammasome by Oxidized LDL or TNF α in Vascular Endothelial Cells through a PXR-Dependent Mechanism

Mol Pharmacol. 2017 Sep;92(3):256-264. doi: 10.1124/mol.116.108100. Epub 2017 May 25.

Authors

Affiliations

¹ 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.).
² 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.) nanpingwang2003@yahoo.com xiaolei0122@xjtu.edu.cn.

PMID: 28546421
DOI: 10.1124/mol.116.108100

Abstract

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 (TNFα) activated the NLRP3 inflammasome in ECs. Simvastatin or mevastatin significantly suppressed the effects of ox-LDL or TNFα 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 IκBα-attenuated ox-LDL- or TNFα-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 TNFα in ECs, providing a new mechanism for the cardiovascular benefit of statins.

MeSH terms

Cells, Cultured
Endothelial Cells / metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Lipoproteins, LDL / antagonists & inhibitors*
Lipoproteins, LDL / pharmacology
NF-kappa B / physiology
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / physiology
Pregnane X Receptor
Promoter Regions, Genetic
Receptors, Steroid / agonists
Receptors, Steroid / physiology*
Scavenger Receptors, Class E / physiology
Signal Transduction / drug effects
Tumor Necrosis Factor-alpha / antagonists & inhibitors*
Tumor Necrosis Factor-alpha / pharmacology

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lipoproteins, LDL
NF-kappa B
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
OLR1 protein, human
Pregnane X Receptor
Receptors, Steroid
Scavenger Receptors, Class E
Tumor Necrosis Factor-alpha
oxidized low density lipoprotein