title: 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.
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors: Yang
authors: Y
authors: Chen
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors: Ashley L
authors: AL
authors: Pitzer
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.|Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA.
authors: Xiang
authors: X
authors: Li
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors: Pin-Lan
authors: PL
authors: Li
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors: Lei
authors: L
authors: Wang
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.|Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA.
authors: Yang
authors: Y
authors: Zhang
mesh_terms: D054392:Adipokines / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D003331:Coronary Vessels / Q000378:metabolism; D059305:Diet, High-Fat; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D007365:Intercellular Junctions / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000494:pharmacology; D034622:RNA Interference; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D054392:Adipokines; C000593873:Ager protein, mouse; D024243:HMGB1 Protein; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D062725:Tight Junction Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D054409:Nicotinamide Phosphoribosyltransferase
keywords: Nlrp3 inflammasome; endothelium; obesity; tight junction proteins; visfatin