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

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 (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.

Exogenous nanoparticles and endogenous crystalline molecules as danger signals for the NLRP3 inflammasomes

“…Duewell et al () showed that deficiency of inflammasome‐related molecules, such as NLRP3, ASC, or IL‐1β, attenuated the development of atherosclerotic lesions in mice, indicating that NLRP3 inflammasomes, induced by cholesterol crystals, play an important role in the progression of atherosclerosis. In addition to macrophages, cholesterol crystals also markedly increase the formation and activation of NLRP3 inflammasomes in carotid arterial endothelial cells, as shown by increased colocalization of NLRP3 with ASC or caspase‐1, enhanced caspase‐1 activity, and elevated IL‐1β secretion in mice (Koka et al, ), suggesting an essential role for endothelial inflammasome activation in arterial dysfunction and atherosclerosis (S. Wang et al, ).…”

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

“…These types of modified LDL mimic damageand pathogen-associated molecular patterns, thus serving as the primary sources of cholesterol accumulation and chronic inflammation in atherosclerotic plaques (Tabas et al, 2015). In addition, these modified LDLs can cause oxidative stress, inflammation, NLRP3 inflammasome activation, and immune response, thus amplifying the vicious cycle of atherogenic cellular events (Steinberg and Witztum, 2010;Wang et al, 2017h). In addition to modified LDL, interleukin 1 (IL-1) (IL-1a and IL-1b) also drives vascular inflammation, with IL-1a mainly being involved in arterial remodeling during the early phase of atherosclerosis, whereas IL-1b drives inflammation and atheroprogression to advanced state of atherosclerosis (Vromman et al, 2019).…”

Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

“…For example, PXR in early cancer development could function in an opposite manner when compared in late cancer activation. This kind of behavior is seen with inflammasomes (e.g., NLRP3) [ 80 , 81 , 82 , 83 ]. Differences in outcome-specific PXR activation is also possible, for example, PXR inhibits inflammation and inflammation-induced colitis [ 84 ], but promotes late sporadic colon cancer [ 15 ].…”