title: Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis.
abstract: Although much progress has been made in identifying the mechanisms that trigger endothelial activation and inflammatory cell recruitment during atherosclerosis, less is known about the intrinsic pathways that counteract these events. Here we identified NOTCH1 as an antagonist of endothelial cell (EC) activation. NOTCH1 was constitutively expressed by adult arterial endothelium, but levels were significantly reduced by high-fat diet. Furthermore, treatment of human aortic ECs (HAECs) with inflammatory lipids (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine [Ox-PAPC]) and proinflammatory cytokines (TNF and IL1β) decreased Notch1 expression and signaling in vitro through a mechanism that requires STAT3 activation. Reduction of NOTCH1 in HAECs by siRNA, in the absence of inflammatory lipids or cytokines, increased inflammatory molecules and binding of monocytes. Conversely, some of the effects mediated by Ox-PAPC were reversed by increased NOTCH1 signaling, suggesting a link between lipid-mediated inflammation and Notch1. Interestingly, reduction of NOTCH1 by Ox-PAPC in HAECs was associated with a genetic variant previously correlated to high-density lipoprotein in a human genome-wide association study. Finally, endothelial Notch1 heterozygous mice showed higher diet-induced atherosclerosis. Based on these findings, we propose that reduction of endothelial NOTCH1 is a predisposing factor in the onset of vascular inflammation and initiation of atherosclerosis.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Briot
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Seki
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Karen
authors.initials: K
authors.lastname: Hoi
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Mack
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Howard Hughes Medical Institute, Los Angeles, CA 90095.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Howard Hughes Medical Institute, Los Angeles, CA 90095.
authors.forename: Jason
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Howard Hughes Medical Institute, Los Angeles, CA 90095.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Fishbein
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Ladan
authors.initials: L
authors.lastname: Vakili
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Howard Hughes Medical Institute, Los Angeles, CA 90095.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Berliner
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095 arispe@mcdb.ucla.edu.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
mesh_terms: D000328:Adult; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D008055:Lipids / Q000097:blood*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D010713:Phosphatidylcholines / Q000494:pharmacology; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D008055:Lipids; D010713:Phosphatidylcholines; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine