Rheumatology Advance Access originally published online on June 29, 2005
Rheumatology 2005 44(10):1238-1244; doi:10.1093/rheumatology/keh722
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Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model
Pharmacology Department, Faculty of Medical Sciences, New University of Lisbon, Lisbon, Portugal, 1 Centre for Rheumatology, Department of Medicine, University College London, London, 2 Academic Department of Rheumatology, Leeds University Teaching Hospitals, Leeds, UK, 3 Department of Medicine, Division of Rheumatology, University of California at Los Angeles, CA, 4 Section of Nephrology, Department of Medicine, The University of Chicago, Chicago, IL, USA and 5 Division of Rheumatology, Department of Medicine, The Research Institute of the McGill University Health Centre, Montreal, Canada.
Correspondence to: J. Delgado Alves, Faculdade de Ciências Medicas, Departamento Farmacologia, Campo Mártires da Pátria, 1301169-056 Lisboa, Portugal. E-mail: jdalves.farm{at}fcm.unl.pt
Objective. Oxidative stress contributes to atherosclerosis, and evidence of enhanced oxidative stress exists in antiphospholipid syndrome (APS). In a non-lupus murine model, we evaluated whether anticardiolipin (aCL) antibodies could affect the oxidant/antioxidant balance as an early biochemical step of APS.
Methods. Hybridomas producing human and murine aCL and anti-ß2-glycoprotein I (aß2-GPI) monoclonal antibodies were injected into three groups of five female BALB/c severe combined immunodeficiency (SCID) mice. Corresponding hybridomas secreting non-antiphospholipid antibodies of the same isotype were employed as controls. Sera and organs were collected after 30 days. Paraoxonase (PON) activity, peroxynitrite, superoxide, nitric oxide (NO) and nitrotyrosine were measured in plasma. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) was assessed by western blot and immunohistochemistry.
Results. PON activity and NO (sum of nitrate and nitrite) levels were reduced in the human aCL IgG group (P<0.002 and P<0.04, respectively), whilst peroxynitrite and superoxide and expression of total antioxidant capacity of plasma were increased (P<0.01). PON and NO were decreased in the murine aß2-GPI IgG and IgM aCL groups (P<0.03 and P<0.05, respectively). Nitrotyrosine was elevated in the human aCL IgG group (P<0.03). Western blotting showed reduced iNOS expression in the hearts of the IgG aCL group, confirmed by immunostaining. PON inversely correlated with IgG aCL titres (P<0.001), superoxide (P<0.008) and peroxynitrite levels (P<0.0009). Peroxynitrite and total IgG aCL were independent predictors of PON (P<0.0009 and P<0.02, respectively). Superoxide was the only independent predictor of NO (P<0.008) and of nitrotyrosine (P<0.002).
Conclusion. aCL antibodies are associated with the decreased PON activity and reduced NO that may occur in the preclinical phase of APS.
KEY WORDS: Antiphospholipid antibodies, Oxidative stress, Nitric oxide, Total antioxidant capacity, Paraoxonase
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