Abstract
ObjectivesTo determine mechanisms involved in endothelial dysfunction (ED) during the course of arthritis and to investigate the link between cytokines, chemokines and osteoprotegerin.Approach and ResultsExperiments were conducted on aortic rings at day 4 (preclinical), day 11 (onset of disease), day 33 (acute disease) and day 90 (chronic disease) after adjuvant-induced arthritis (AIA) in Lewis rats. At day 4, the unique vascular abnormality was a reduced norepinephrine-induced constriction. At day 11, endothelial function assessed by the relaxation to acetylcholine was normal despite increased cyclo-oxygenase-2 activity (COX-2) and overproduction of superoxide anions that was compensated by increased nitric oxide synthase (NOS) activity. At day 33, ED apparition coincides with the normalization of NOS activity. At day 90, ED was only observed in rats with a persisting imbalance between endothelial NOS and COX-2 pathways and higher plasma levels of IL-1β and TNFα. Plasma levels of IL-1β, TNFα and MIP-1α negatively correlated with Ach-induced relaxation throughout the course of AIA.ConclusionsOur data identified increased endothelial NOS activity as an important compensatory response that opposes the ED in the early arthritis. Thereafter, a cross-talk between endothelial COX-2/NOS pathways appears as an important element for the occurrence of ED. Our results encourage determining the clinical value of IL-1β, TNFα and MIP-1α as biomarkers of ED in RA.
Highlights
Rheumatoid arthritis (RA) is the most common systemic autoimmune disease resulting in excessive cardiovascular (CV) events and mortality [1]
Thereafter, a cross-talk between endothelial COX-2/nitric oxide synthase (NOS) pathways appears as an important element for the occurrence of endothelial dysfunction (ED)
Our results encourage determining the clinical value of IL-1β, TNFα and MIP-1α as biomarkers of ED in RA
Summary
Rheumatoid arthritis (RA) is the most common systemic autoimmune disease resulting in excessive cardiovascular (CV) events and mortality [1]. We reported that ED was absent in the early symptomatic stages of the disease but became detectable at the time of maximal inflammation in AIA [6]. The time at which changes in endothelial phenotype appear during the course of arthritis is not known whereas its knowledge may help to identify the “window of opportunity” for CV risk prevention in RA. Whether these phenotypes changes persist when disease activity decreased is unknown
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