title: Etanercept improves endothelial function via pleiotropic effects in rat adjuvant-induced arthritis.
abstract: To determine the effect of etanercept on endothelial dysfunction and on traditional cardiovascular (CV) risk factors in the adjuvant-induced arthritis (AIA) rat model.
  
  
  
  At the first signs of arthritis, etanercept (10 mg/kg/3 days, s.c.) or saline was administered for 3 weeks in AIA rats. Body weights and arthritis scores were monitored daily. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of nitric oxide synthase (NOS), cyclo-oxygenase (COX-2), arginase, endothelium-derived hyperpolarizing factor and superoxide anions (O2 (-)°) production. Aortic expression of endothelial nitic oxide synthase (eNOS), Ser1177-phospho-eNOS, COX-2, arginase-2, p22(phox) and p47(phox) was evaluated by western blotting analysis. Blood pressure, heart rate and blood levels of triglycerides, cholesterol and glucose were measured.
  
  
  
  Etanercept significantly reduced arthritis score (P < 0.001). It improved Ach-induced relaxation (P < 0.05) as a result of increased NOS activity, decreased COX-2/arginase activities and decreased O2 (-)° production. These functional effects relied on increased eNOS expression and phosphorylation, and decreased COX-2, arginase-2 and p22(phox) expressions. No correlation was found between arthritis score and Ach-induced relaxation. The treatment did not change triglycerides, cholesterol and glucose levels, but significantly increased systolic blood pressure and heart rate (P < 0.05).
  
  
  
  Our data demonstrated that efficient dosage of etanercept on inflammatory symptoms improved endothelial function in AIA. This beneficial effect on endothelial function is disconnected from its impact on CV risk factors and relates to pleiotropic effects of etanercept on endothelial pathways. These results suggest that etanercept could be a good choice for patients with rheumatoid arthritis at high risk of CV events.
authors.affiliation: EA 4267 FDE, FHU INCREASE, University of Bourgogne Franche-Comté, Besancon.
authors.forename: Perle
authors.initials: P
authors.lastname: Totoson
authors.affiliation: EA 4267 FDE, FHU INCREASE, University of Bourgogne Franche-Comté, Besancon.
authors.forename: Katy
authors.initials: K
authors.lastname: Maguin-Gaté
authors.affiliation: INSERM U1093, University of Bourgogne Franche-Comté, Dijon.
authors.forename: Anne
authors.initials: A
authors.lastname: Prigent-Tessier
authors.affiliation: INSERM U1093, University of Bourgogne Franche-Comté, Dijon.
authors.forename: Alice
authors.initials: A
authors.lastname: Monnier
authors.affiliation: EA 4267 FDE, FHU INCREASE, University of Bourgogne Franche-Comté, Besancon Service de Rhumatologie, CHRU Besançon.
authors.forename: Frank
authors.initials: F
authors.lastname: Verhoeven
authors.affiliation: INSERM U1093, University of Bourgogne Franche-Comté, Dijon.
authors.forename: Christine
authors.initials: C
authors.lastname: Marie
authors.affiliation: Service de Rhumatologie, CHRU Besançon EA 4266, University of Bourgogne Franche-Comté, Besancon, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wendling
authors.affiliation: EA 4267 FDE, FHU INCREASE, University of Bourgogne Franche-Comté, Besancon cdemouge@univ-fcomte.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Demougeot
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001011:Aorta / Q000201:enzymology; D001119:Arginase / Q000187:drug effects; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000209:etiology; D051546:Cyclooxygenase 2 / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D000068800:Etanercept / Q000494:pharmacology*; D058685:Genetic Pleiotropy / Q000187:drug effects*; D008297:Male; D019255:NADPH Oxidases / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D018501:Antirheumatic Agents; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D001119:Arginase; D000068800:Etanercept
keywords: adjuvant-induced arthritis; endothelial dysfunction; etanercept; mechanisms