Background/Purpose:

Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) morbidity and mortality secondary to endothelial dysfunction (ED). Growing evidence suggests that TNFα-inhibitors may reduce ED in RA patients, but the underlying mechanisms are still unclear. In this study, we investigated the impact of Etanercept on endothelial function and related pathways as well as on traditional CV risk factors in the adjuvant-induced arthritis (AIA) rat model.

Methods:

AIA was induced by an intradermal injection of Mycobacterium butyricum in the tail of male Lewis rats. At the first signs of arthritis (day 11 post-immunization), Etanercept (10 mg/kg/3 days, sc) was administered for 21 days. AIA control rats received saline. Body weights and arthritis scores were daily monitored. At the end of treatment, blood pressure was measured by invasive method. Blood was collected to measure triglycerides, cholesterol and glucose levels. Endothelial function was studied in aortic rings relaxed with cumulative concentrations of acetylcholine (Ach, 10^-11-10^-4 moles/liter) in the presence or not of inhibitors of nitric oxide synthase (eNOS), cyclooxygenase-2 (COX-2), Arginase, endothelium-derived hyperpolarizing factor (EDHF) and superoxide anions (O₂^-°) production. Aortic expression of eNOS, phospho-ser1177-eNOS, COX-2, Arginase-2, p22phox and p47phox was evaluated by western blotting analysis.

Results:

As compared to control AIA, Etanercept significantly improved Ach-induced relaxation (p<0.05) as a result of increased NOS activity, decreased COX-2 and arginase activities, and decreased O₂^-° production. These functional effects relied on increased eNOS expression and phosphorylation, decreased COX-2, Arginase-2 and p22phox expressions, respectively. By contrast, there was no change in EDHF production and p47phox expression. Etanercept reduced arthritis score by about 34% (p<0.001). Of note, no correlation was found between arthritis score and Ach-induced relaxation (r=-0.195; p=0.246, all AIA rats). The treatment did not affect triglycerides, cholesterol and glucose levels but significantly increased systolic blood pressure (p<0.05).

Conclusion:

Our data show the involvement of the NOS, Arginase, COX-2 and NADPH oxidase pathways in Etanercept-induced improvement in endothelial in AIA even though the pivotal common effector of these pathways remains to be identified. They also reveal that the beneficial effect on endothelial function is disconnected from its impact on traditional CV risk factors which are worsened or unchanged. This latter result, associated with a lack of correlation between endothelial function and arthritic scores suggests that the vascular effect of Etanercept is, at least in part, independent on the reduction of disease severity and other traditional CV risk factors. From a therapeutic point of view, they suggest that Etanercept could be a good choice in RA patients at high risk of CV events.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cardiovascular-effects-of-etanercept-in-an-animal-model-of-rheumatoid-arthritis-mechanisms-involved/