title: Endothelial NLRP3 inflammasome activation and enhanced neointima formation in mice by adipokine visfatin.
abstract: Inflammasomes serve as an intracellular machinery to initiate inflammatory response to various danger signals. The present study tested whether an inflammasome centered on nucleotide oligomerization domain-like receptor protein 3 (NLRP3) triggers endothelial inflammatory response to adipokine visfatin, a major injurious adipokine during obesity. NLRP3 inflammasome components were abundantly expressed in cultured mouse microvascular endothelial cells, including NLRP3, apoptosis-associated speck-like protein, and caspase-1. These NLRP3 inflammasome molecules could be aggregated to form an inflammasome complex on stimulation of visfatin, as shown by fluorescence confocal microscopy and size exclusion chromatography. Correspondingly, visfatin significantly increased caspase-1 activity and IL-1β release in microvascular endothelial cells, indicating an activation of NLRP3 inflammasomes. In animal experiments, direct infusion of visfatin in mice with partially ligated left carotid artery were found to have significantly increased neointimal formation, which was correlated with increased NLRP3 inflammasome formation and IL-1β production in the intima. Further, visfatin-induced neointimal formation, endothelial inflammasome formation, and IL-1β production in mouse partially ligated left carotid artery were abolished by caspase-1 inhibition, local delivery of apoptosis-associated speck-like protein shRNA or deletion of the ASC gene. In conclusion, the formation and activation of NLRP3 inflammasomes by adipokine visfatin may be an important initiating mechanism to turn on the endothelial inflammatory response leading to arterial inflammation and endothelial dysfunction in mice during early stage obesity.
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Boini
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Justine M
authors.initials: JM
authors.lastname: Abais
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia. Electronic address: pli@vcu.edu.
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
mesh_terms: D054392:Adipokines / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002850:Chromatography, Gel; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D055806:Microvessels / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058426:Neointima / Q000473:pathology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
chemical_list: D054392:Adipokines; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D034741:RNA, Small Interfering; D013481:Superoxides; D054409:Nicotinamide Phosphoribosyltransferase; D020170:Caspase 1