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Aspirin alleviates endothelial gap junction dysfunction through inhibition of NLRP3 inflammasome activation in LPS-induced vascular injury.

ABSTRACT: The loss of endothelial connective integrity and endothelial barrier dysfunction can lead to increased vascular injury, which is related to the activation of endothelial inflammasomes. There are evidences that low concentrations of aspirin can effectively prevent cardiovascular diseases. We hypothesized that low-dose aspirin could ameliorate endothelial injury by inhibiting the activation of NLRP3 inflammasomes and ultimately prevent cardiovascular diseases. Microvascular endothelial cells were stimulated by lipopolysaccharide (2??g/mL) and administrated by 0.1-2?mmol/L aspirin. The wild type mice were stimulated with LPS (100??g/kg/day), and 1?h later treated with aspirin (12.5, 62.5, or 125?mg/kg/day) and dexamethasone (0.0182?mg/kg/day) for 7 days. Plasma and heart were harvested for measurement of ELISA and immunofluorescence analyses. We found that aspirin could inhibit NLRP3 inflammasome formation and activation in vitro in dose-dependent manner and has correlation between the NLRP3 inflammasome and the ROS/TXNIP pathway. We also found that low-concentration aspirin could inhibit the formation and activation of NLRP3 inflammasome and restore the expression of the endothelial tight junction protein zonula occludens-1/2 (ZO1/2). We assume that aspirin can ameliorate the endothelial layer dysfunction by suppressing the activation of NLRP3 inflammasome.

SUBMITTER: Zhou X

PROVIDER: S-EPMC6664043 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Aspirin alleviates endothelial gap junction dysfunction through inhibition of NLRP3 inflammasome activation in LPS-induced vascular injury.

Zhou Xing X Wu Yanjiao Y Ye Lifeng L Wang Yunting Y Zhang Kaimin K Wang Lingjun L Huang Yi Y Wang Lei L Xian Shaoxiang S Zhang Yang Y Chen Yang Y

Acta pharmaceutica Sinica. B 20190228 4

The loss of endothelial connective integrity and endothelial barrier dysfunction can lead to increased vascular injury, which is related to the activation of endothelial inflammasomes. There are evidences that low concentrations of aspirin can effectively prevent cardiovascular diseases. We hypothesized that low-dose aspirin could ameliorate endothelial injury by inhibiting the activation of NLRP3 inflammasomes and ultimately prevent cardiovascular diseases. Microvascular endothelial cells were ...[more]

PMID: 31384532

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Project description:Recent studies have indicated that the inflammasome plays a critical role in the pathogenesis of vascular diseases. However, the pathological relevance of this inflammasome activation, particularly in vascular cells, remains largely unknown. Here, we investigated the role of endothelial (Nucleotide-binding Oligomerization Domain) NOD-like receptor family pyrin domain containing three (Nlrp3) inflammasomes in modulating inter-endothelial junction proteins, which are associated with endothelial barrier dysfunction, an early onset of obesity-associated endothelial injury. Our findings demonstrate that the activation of Nlrp3 inflammasome by visfatin markedly decreased the expression of inter-endothelial junction proteins including tight junction proteins ZO-1, ZO-2 and occludin, and adherens junction protein VE-cadherin in cultured mouse vascular endothelial (VE) cell monolayers. Such visfatin-induced down-regulation of junction proteins in endothelial cells was attributed to high mobility group box protein 1 (HMGB1) release derived from endothelial inflammasome-dependent caspase-1 activity. Similarly, in the coronary arteries of wild-type mice, high-fat diet (HFD) treatment caused a down-regulation of inter-endothelial junction proteins ZO-1, ZO-2, occludin and VE-cadherin, which was accompanied with enhanced inflammasome activation and HMGB1 expression in the endothelium as well as transmigration of CD43(+) T cells into the coronary arterial wall. In contrast, all these HFD-induced alterations in coronary arteries were prevented in mice with Nlrp3 gene deletion. Taken together, these data strongly suggest that the activation of endothelial Nlrp3 inflammasomes as a result of the increased actions of injurious adipokines such as visfatin produces HMGB1, which act in paracrine or autocrine fashion to disrupt inter-endothelial junctions and increase paracellular permeability of the endothelium contributing to the early onset of endothelial injury during metabolic disorders such as obesity or high-fat/cholesterol diet.

Project description:Background: The pathogenesis of sepsis-associated encephalopathy (SAE) is complicated, while the efficacy of current treatment technologies is poor. Therefore, the discovery of related targets and the development of new drugs are essential. Methods: A mouse model of SAE was constructed by intraperitoneal injection of lipopolysaccharide (LPS). LPS treatment of microglia was used to build an in vitro model of inflammation. Nine-day survival rates, behavioral testing, transmission electron microscopy (TEM), immunohistochemical (IHC), immunofluorescence (IF), and ELISA were performed. The expression levels of Occludin, Claudin 5, NLRP3, caspase-1, and ASC genes and proteins were detected by RT-qPCR or Western blot. Caspase-1 P10 (Casp-1 P10) protein expression was detected. 16S rDNA sequencing and gas chromatography-mass spectrometer (GC-MS) were used to analyze the gut microbiota and metabolism. Flow cytometric experiment and Cell Counting Kit-8 (CCK8) assay were performed. Results: NU9056 improved the survival rate of mice and alleviated LPS-induced cognitive impairment, anxiety, and depression in vivo. The tight junctions were thickened via NU9056 treatment. Further, the mRNAs and proteins expression levels of Occludin and Claudin 5 were up-regulated by NU9056. NU9056 increased the expression level of DCX. The expression levels of Iba-1, NLRP3, IL-1β, ASC, and Casp-1 P10 were down-regulated by NU9056. The composition of the gut microbiota changed. Kyoto Encyclopedia of Genes and Genomes data predicted that the effects of NU9056 might be related to apoptosis and tight junction pathways. NU9056 up-regulated the concentration of acetate, propionate, and butyrate. NU9056 significantly reduced LPS-induced apoptosis of microglia, the average fluorescence intensity of ROS, and the release of IL-1β and IL-18, while improving cell viability in vitro. Conclusions: NU9056 might effectively alleviate LPS-induced cognitive impairment and emotional disorder in experimental mice by inhibiting the NLRP3 inflammasome. The therapeutic effects may be related to gut microbiota and derived metabolites. NU9056 might be a potential drug of SAE prevention.

Dataset Information

Aspirin alleviates endothelial gap junction dysfunction through inhibition of NLRP3 inflammasome activation in LPS-induced vascular injury.

Publications

Aspirin alleviates endothelial gap junction dysfunction through inhibition of NLRP3 inflammasome activation in LPS-induced vascular injury.

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