Infliximab improves endothelial dysfunction in a mouse model of antiphospholipid syndrome: Role of reduced oxidative stress

Ygal Benhamou (1, 2) , Sébastien Miranda (3, 2) , Guillaume Armengol (3, 2) , Najah Harouki (2) , Laurent Drouot (4) , Noel Zahr (5) , Christian Thuillez (6) , Olivier Boyer (4) , Hervé Levesque (1, 2) , Robinson Joannides (2) , Vincent Richard (7)

1 Service de Médecine Interne [CHU Rouen]
2 EnVI - Endothélium, valvulopathies et insuffisance cardiaque
3 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
4 Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes
5 CHU Pitié-Salpêtrière [AP-HP]
6 Pharmacologie des Dysfonctionnements Endotheliaux et Myocardiques
7 Institut Pasteur de Dakar

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 (5 μg/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.

Domaines: Cardiologie et système cardiovasculaire; Physiologie [q-bio.TO]; Biotechnologies; Immunologie; Sciences pharmaceutiques

Ygal Benhamou, Sébastien Miranda, Guillaume Armengol, Najah Harouki, Laurent Drouot, et al.. Infliximab improves endothelial dysfunction in a mouse model of antiphospholipid syndrome: Role of reduced oxidative stress. Vascular Pharmacology, 2015, 71, pp.93-101. ⟨10.1016/j.vph.2015.03.014⟩. ⟨inserm-02296630⟩