title: Trans-fatty acid promotes thrombus formation in mice by aggravating antithrombogenic endothelial functions via Toll-like receptors.
abstract: METHODS
  Since excessive intake of trans-fatty acid (TFA) increases the risk of myocardial infarction, we investigated the effects of TFA on thrombus formation using animal and cell culture experiments.
  
  
  RESULTS
  C57BL/6 mice were fed a diet containing TFA or cis-fatty acid (5% each of total calories) or a chow diet for 4 weeks, and thrombus formation was induced in the carotid artery by He-Ne laser irradiation. The high-TFA diet significantly promoted thrombus formation in the carotid artery compared to the chow or cis-fatty acid diet. TFA activated the inflammatory signaling pathway in cultured endothelial cells and in mice; aortic gene expression levels of antithrombogenic molecules, including thrombomodulin and tissue factor pathway inhibitor, were decreased, and the expression levels of prothrombogenic molecules were increased in TFA-treated mice. TFA markedly upregulated the prothrombogenic molecules and downregulated the antithrombogenic molecules in endothelial cells. In addition, TFA induced phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor-κB. The TFA-activated signal pathways and prothrombogenic phenotypic changes of endothelial cells were inhibited by genetic or pharmacological inactivation of Toll-like receptors 2 and 4.
  
  
  CONCLUSIONS
  TFA aggravates the antithrombogenic phenotypes of vascular endothelial cells via Toll-like receptors and promotes thrombus formation in mice.
authors.affiliation: Division of Cardiovascular Medicine, Graduate School of Medicine, Kobe University, Kobe, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kondo
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishida
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yasuda
authors.forename: Hideto
authors.initials: H
authors.lastname: Nakajima
authors.forename: Kenta
authors.initials: K
authors.lastname: Mori
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Takeshige
authors.initials: T
authors.lastname: Mori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Monguchi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shinohara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Irino
authors.forename: Ryuji
authors.initials: R
authors.lastname: Toh
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Rikitake
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kiyomizu
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yamamoto
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirata
mesh_terms: D000818:Animals; D004032:Diet; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D044242:Trans Fatty Acids / Q000009:adverse effects*; D015854:Up-Regulation
chemical_list: D008074:Lipoproteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018180:Thrombomodulin; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D044242:Trans Fatty Acids; C051928:lipoprotein-associated coagulation inhibitor; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Endothelial dysfunction; Inflammation; Thrombosis; Toll-like receptor; Trans-fatty acid