title: Role of Toll-like receptors 2 and 4 in mediating endothelial dysfunction and arterial remodeling in primary arterial antiphospholipid syndrome.
abstract: OBJECTIVE
  To assess the role of Toll-like receptors (TLRs) in antiphospholipid antibody (aPL)-mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).
  
  
  METHODS
  Forty-eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild-type (WT) and TLR-knockout mice.
  
  
  RESULTS
  APS patients had endothelial dysfunction, arterial stiffening, and hypertrophy, as evidenced by decreased brachial artery endothelium-dependent flow-mediated dilation (FMD) and increased aortic pulse wave velocity and carotid intima-media thickness (IMT), as compared with controls. Plasma samples from APS patients revealed decreased nitric oxide (NO) availability and a pro-oxidative, proinflammatory, and prothrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, tumor necrosis factor α levels, and tissue factor (TF) levels. Furthermore, TLR pathway activation was found in APS patients with increased TLR-2 and TLR-4 messenger RNA expression and increased protein levels of the activated TLR transduction protein interleukin-1 receptor-associated kinase 1 in peripheral blood mononuclear cells. Moreover, agonist-stimulated cell-surface expression of TLR-2 and TLR-4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively associated with FMD. Finally, aPL injection decreased mesenteric endothelium-dependent relaxation and increased TF expression in WT mice but not in TLR-2- or TLR-4-knockout mice.
  
  
  CONCLUSIONS
  This translational study supports the notion that TLR-2 and TLR-4 play a role in mediating vascular abnormalities in patients with primary arterial APS. TLRs thus constitute a promising pharmacologic target for preventing cardiovascular complications in APS.
authors.affiliation: Rouen University Hospital, INSERM U1096, University of Rouen, and Centre d'Investigation Clinique, INSERM 1404, Rouen, France.
authors.forename: Ygal
authors.initials: Y
authors.lastname: Benhamou
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bellien
authors.forename: Guillaume
authors.initials: G
authors.lastname: Armengol
authors.forename: Ebba
authors.initials: E
authors.lastname: Brakenhielm
authors.forename: Sahil
authors.initials: S
authors.lastname: Adriouch
authors.forename: Michele
authors.initials: M
authors.lastname: Iacob
authors.forename: Isabelle
authors.initials: I
authors.lastname: Remy-Jouet
authors.forename: Véronique
authors.initials: V
authors.lastname: Le Cam-Duchez
authors.forename: Christelle
authors.initials: C
authors.lastname: Monteil
authors.forename: Sylvanie
authors.initials: S
authors.lastname: Renet
authors.forename: Fabienne
authors.initials: F
authors.lastname: Jouen
authors.forename: Laurent
authors.initials: L
authors.lastname: Drouot
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Menard
authors.forename: Jeanne-Yvonne
authors.initials: JY
authors.lastname: Borg
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.forename: Hervé
authors.initials: H
authors.lastname: Levesque
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.forename: Robinson
authors.initials: R
authors.lastname: Joannidès
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000494:pharmacology / Q000502:physiology; D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000503:physiopathology*; D001916:Brachial Artery / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000276:immunology / Q000503:physiopathology*; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D063177:Pulse Wave Analysis; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D066253:Vascular Remodeling / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D017152:Antibodies, Antiphospholipid; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4