title: Infliximab improves endothelial dysfunction in a mouse model of antiphospholipid syndrome: Role of reduced oxidative stress.
abstract: Antiphospholipid syndrome (APS), induces endothelial dysfunction, oxidative stress and systemic inflammation that may be mediated by TNFα. Thus, we investigated the possible protective effect of the anti-TNFα antibody infliximab (5μg/g) on endothelial function in a mouse APS model (induced by injection of purified human anti-β2GP1-IgG). Seven days after anti-β2GPI-IgG injection, we observed an increase in plasma sVCAM-1 and sE-selectin levels and in aortic mRNA expression of VCAM-1 and E-selectin. This was associated with a decreased endothelium-dependent relaxation of isolated mesenteric arteries to acetylcholine, together with decreased mesenteric eNOS mRNA expression and increased eNOS uncoupling, accompanied by increased iNOS and gp91phox mRNA and increased left ventricular GSH/GSSH ratio. Infliximab significantly improved the NO-mediated relaxing responses to acetylcholine, and induced a decrease in iNOS and gp91phox mRNA expression. The õpro-adhesive and pro-coagulant phenotypes induced by the anti-β2GP1-IgG were also reversed. This study provides the first evidence that TNFα antagonism improves endothelial dysfunction in APS and suggests that endothelial dysfunction is mediated by TNFα and oxidative stress. Therefore, infliximab may be of special relevance in clinical practice.
authors: Inserm U1096, Rouen, France; Rouen University Hospital, Department of Internal Medicine, Rouen France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France. Electronic address: ygal.benhamou@chu-rouen.fr.
authors: Ygal
authors: Y
authors: Benhamou
authors: Inserm U1096, Rouen, France; Rouen University Hospital, Department of Internal Medicine, Rouen France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors: Sébastien
authors: S
authors: Miranda
authors: Inserm U1096, Rouen, France; Rouen University Hospital, Department of Internal Medicine, Rouen France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors: Guillaume
authors: G
authors: Armengol
authors: Inserm U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors: Najah
authors: N
authors: Harouki
authors: University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France; Inserm U905, Rouen, France.
authors: Laurent
authors: L
authors: Drouot
authors: Pharmacovigilance Unit, La Pitié-Salpétrière Hospital, AP-HP, Paris France.
authors: Noel
authors: N
authors: Zahr
authors: Rouen University Hospital, Department of Internal Medicine, Rouen France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors: Christian
authors: C
authors: Thuillez
authors: University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France; Inserm U905, Rouen, France.
authors: Olivier
authors: O
authors: Boyer
authors: Inserm U1096, Rouen, France; Rouen University Hospital, Department of Internal Medicine, Rouen France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors: Hervé
authors: H
authors: Levesque
authors: Rouen University Hospital, Department of Internal Medicine, Rouen France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors: Robinson
authors: R
authors: Joannides
authors: Rouen University Hospital, Department of Internal Medicine, Rouen France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors: Vincent
authors: V
authors: Richard
mesh_terms: D000818:Animals; D016736:Antiphospholipid Syndrome / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000069285:Infliximab / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab
keywords: Antiphospholipid antibodies; Endothelium; Infliximab; Oxidative stress; Tumor necrosis factor alpha