title: Adiponectin inhibits macrophage tissue factor, a key trigger of thrombosis in disrupted atherosclerotic plaques.
abstract: OBJECTIVE
  Adiponectin (APN) is an adipocytokine with anti-atherogenic and anti-inflammatory properties. Hypoadiponectinemia may associate with increased risk for coronary artery disease (CAD) and acute coronary syndrome (ACS). Tissue factor (TF) initiates thrombus formation and facilitates luminal occlusion after plaque rupture, a common cause of fatal ACS. This study tested the hypothesis that APN influences TF expression by macrophages (MΦ), inflammatory cells found in atheromatous plaques.
  
  
  METHODS
  Human monocyte-derived MΦ or RAW 264.7 cells transfected with TF promoter construct, pretreated with a physiological range of recombinant APN (1-10 μg/ml), received LPS stimulation. TF mRNA and protein levels were quantified by real-time RT-PCR and ELISA. TF pro-coagulant activity was evaluated by one-step clotting assay. TF promoter activity was determined by a dual-luciferase reporter assay. Immunoblot analyses assessed intracellular signaling pathways.
  
  
  RESULTS
  APN treatment suppressed TF mRNA expression and protein production in LPS-stimulated human MΦ, compared to vehicle controls. APN treatment also significantly reduced TF pro-coagulant activity in lysates of LPS-stimulated human MΦ, compared to vehicle controls. Moreover, APN suppressed TF promoter activity in LPS-stimulated MΦ compared to controls. APN suppressed phosphorylation and degradation of IκB-α in LPS-stimulated MΦ.
  
  
  CONCLUSIONS
  APN reduces thrombogenic potential of MΦ by inhibiting TF expression and activity. These observations provide a potential mechanistic link between low APN levels and the thrombotic complications of atherosclerosis.
authors.affiliation: Department of Bioregulation, Nippon Medical School, Kawasaki, Kanagawa, Japan. yokamoto@nms.ac.jp
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Okamoto
authors.forename: So
authors.initials: S
authors.lastname: Ishii
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.forename: Harumi
authors.initials: H
authors.lastname: Katsumata
authors.forename: Makoto
authors.initials: M
authors.lastname: Fukushima
authors.forename: Shinji
authors.initials: S
authors.lastname: Kihara
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Shiro
authors.initials: S
authors.lastname: Minami
mesh_terms: D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D058226:Plaque, Atherosclerotic; D012333:RNA, Messenger / Q000378:metabolism; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D052242:Adiponectin; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013925:Thromboplastin