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Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: role of HMGB1.

ABSTRACT: 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.

SUBMITTER: Chen Y

PROVIDER: S-EPMC4687695 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: role of HMGB1.

Chen Yang Y Pitzer Ashley L AL Li Xiang X Li Pin-Lan PL Wang Lei L Zhang Yang Y

Journal of cellular and molecular medicine 20150820 12

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 ba ...[more]

PMID: 26293846

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Project description:Visfatin/extracellular-nicotinamide-phosphoribosyltranferase-(eNampt) is a multifaceted adipokine enhanced in type-2-diabetes and obesity. Visfatin/eNampt cause in vitro endothelial dysfunction and vascular inflammation, although whether the same effects are achieved in vivo is unknown. Toll-like receptor-4 (TLR4), a main surface pattern recognition receptor of innate immune system is a potential target for visfatin/eNampt. We studied its capacity to generate vascular dysfunction in vivo, focusing on TLR4 role and downstream activation of nod-like-receptor-protein-3 (NLRP3)-inflammasome. 4 month-old C57BL/6 mice were exposed to 7 days infusion of visfatin/eNampt, alone or together with FK 866 (Nampt enzymatic inhibitor), CLI 095 (TLR4 blocker), MCC 950 (NLRP3-inflammasome inhibitor), or anakinra (interleukin(IL)-1-receptor antagonist). Endothelial dysfunction was tested in isolated microvessels. In human umbilical endothelial cells (HUVEC), proteins related to the NLRP3-inflammasome phosphorylated p-65, NLRP3, caspase-1, pro-IL-1?, and mature IL-1? were determined by Western blot, while the inflammasome related apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC-specks) was studied by immunofluorescence. Impaired endothelium-dependent relaxations were observed in isolated mesenteric microvessels from visfatin/eNampt-infused mice. This effect was attenuated by co-treatment with FK 866 or CLI 095, supporting a role for Nampt enzymatic activity and TLR4 activation. Moreover, cultured HUVEC exposed to visfatin/eNampt showed higher expression and activation of NLRP3-inflammasome. Again, this effect relied on Nampt enzymatic activity and TLR4 activation, and it was abrogated by the inflammasome assembly blockade with MCC 950. The endothelial dysfunction evoked by visfatin/eNampt infusion in vivo was also sensitive to both MCC 950 and anakinra treatments, suggesting that the NLRP3-inflammasome-driven tissular release of IL-1? is the final mediator of endothelial damage. We conclude that Visfatin/eNampt produces in vivo vascular dysfunction in mice by a Nampt-dependent TLR4-mediated pathway, involving NLRP3-inflammasome and paracrine IL-1?. Thus, those targets may become therapeutic strategies for attenuating the adipokine-mediated vascular dysfunction associated to obesity and/or type-2-diabetes.

Dataset Information

Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: role of HMGB1.

Publications

Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: role of HMGB1.

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