title: Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility.
abstract: BACKGROUND
  The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells via sterol regulatory element binding protein 2 (SREBP2).
  
  
  RESULTS
  Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in endothelial cells. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 and NLRP3. Consistently, SREBP2, NADPH oxidase 2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, endothelial cell-specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas.
  
  
  CONCLUSIONS
  Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Xiao
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Ting Yang
authors.initials: TY
authors.lastname: Lin
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Wei-Chi
authors.initials: WC
authors.lastname: Wang
authors.forename: Traci
authors.initials: T
authors.lastname: Marin
authors.forename: Tzu-Pin
authors.initials: TP
authors.lastname: Shentu
authors.forename: Liang
authors.initials: L
authors.lastname: Wen
authors.forename: Brendan
authors.initials: B
authors.lastname: Gongol
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Hsien-Da
authors.initials: HD
authors.lastname: Huang
authors.forename: Joao H F
authors.initials: JH
authors.lastname: Pedra
authors.forename: David A
authors.initials: DA
authors.lastname: Johnson
authors.forename: John Y J
authors.initials: JY
authors.lastname: Shyy
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006439:Hemodynamics / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000276:immunology / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D034741:RNA, Small Interfering / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013314:Stress, Mechanical; D014657:Vasculitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; D058847:Inflammasomes; C550416:MIRN33a microRNA, human; D008562:Membrane Glycoproteins; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D034741:RNA, Small Interfering; C497390:SREBF2 protein, human; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: NLRP3 protein, human; atherosclerosis; endothelial cell; shear stress; sterol regulatory element binding proteins