title: ROS-dependent Syk and Pyk2-mediated STAT1 activation is required for 15(S)-hydroxyeicosatetraenoic acid-induced CD36 expression and foam cell formation.
abstract: 15(S)-Hydroxyeicosatetraenoic acid (15(S)-HETE), the major 15-lipoxygenase 1/2 (15-LO1/2) metabolite of arachidonic acid (AA), induces CD36 expression through xanthine oxidase and NADPH oxidase-dependent ROS production and Syk and Pyk2-dependent STAT1 activation. In line with these observations, 15(S)-HETE also induced foam cell formation involving ROS, Syk, Pyk2, and STAT1-mediated CD36 expression. In addition, peritoneal macrophages from Western diet-fed ApoE(-/-) mice exhibited elevated levels of xanthine oxidase and NADPH oxidase activities, ROS production, Syk, Pyk2, and STAT1 phosphorylation, and CD36 expression compared to those from ApoE(-/-):12/15-LO(-/-) mice and these events correlated with increased lipid deposits, macrophage content, and lesion progression in the aortic roots. Human atherosclerotic arteries also showed increased 15-LO1 expression, STAT1 phosphorylation, and CD36 levels as compared to normal arteries. Together, these findings suggest that 12/15-LO metabolites of AA, particularly 12/15(S)-HETE, might play a crucial role in atherogenesis by enhancing foam cell formation.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Sivareddy
authors.initials: S
authors.lastname: Kotla
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Nikhlesh K
authors.initials: NK
authors.lastname: Singh
authors.affiliation: Department of Pathology, Louisiana State University Health Science Center, 1501 King׳s Hwy, Shreveport, LA 71130, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Traylor
authors.affiliation: Department of Pathology, Louisiana State University Health Science Center, 1501 King׳s Hwy, Shreveport, LA 71130, USA.
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA. Electronic address: rgadipar@uthsc.edu.
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D001092:Arachidonate 12-Lipoxygenase / Q000737:chemistry / Q000502:physiology; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000502:physiology; D015153:Blotting, Western; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D005487:Foam Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000032:analysis; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase
chemical_list: C475064:12-15-lipoxygenase; D001057:Apolipoproteins E; D018955:CD36 Antigens; D006893:Hydroxyeicosatetraenoic Acids; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse
keywords: CD36; Foam cell; ROS; STAT1; Syk