Abstract
BACKGROUND AND PURPOSEExcess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this ‘proof-of-concept’ study, vascular function was characterized in the murine collagen-induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies.EXPERIMENTAL APPROACHMice in the very early stages of arthritis development [and appropriate naïve (non-immunized) age-matched controls] were used in the study. Blood pressure was measured using tail cuff plethysmography. Vascular function in rings of isolated aorta was studied with isometric tension myography. Levels of NO metabolites (NOx), MMP-9 protein and IL-1β in plasma and MMP-9 protein in aortic homogenates were quantified.KEY RESULTSImpaired vascular contractile responses in arthritis were unaffected by ex vivo inhibition of NOS (endothelial/neuronal and inducible) or COX activities. Endothelium-dependent and -independent relaxation, plasma NOx and blood pressure were unaffected by arthritis. Plasma and aortic homogenate MMP-9 protein levels were increased significantly in arthritis. Incubation of aortic tissues from naïve control animals with exogenous MMP-9 impaired subsequent contractile responses, mirroring that observed in arthritis. A role for IL-1β in perpetuating contractile dysfunction and increasing aortic MMP-9 was excluded.CONCLUSIONS AND IMPLICATIONSThese data identify for the first time a relationship between early arthritis and contractile dysfunction and a possible role for MMP-9 therein, in the absence of overt endothelial dysfunction or increased NO production. As such, MMP-9 may constitute a significant target for early intervention in RA patients with a view to decreasing risk of cardiovascular disease.
Highlights
It has long been established that excess morbidity and mortality is associated with rheumatoid arthritis (RA)
In a recent study of RA patients, whilst traditional cardiovascular risk (CVR) factors were shown to predict a new cardiovascular event, the latter was precipitated by high disease activity (Innala et al, 2011)
A recent study suggests that RA equals type 2 diabetes, a disease associated with low-grade systemic inflammation (Kolb and Mandrup-Poulsen, 2010), as an independent risk factor for cardiovascular disease (CVD) (Peters et al, 2009)
Summary
It has long been established that excess morbidity and mortality is associated with rheumatoid arthritis (RA). What seems clear is that the increased CVR in RA is caused by a combination of such factors and the persistently high levels of inflammation that characterizes these individuals. A recent study suggests that RA equals type 2 diabetes, a disease associated with low-grade systemic inflammation (Kolb and Mandrup-Poulsen, 2010), as an independent risk factor for CVD (Peters et al, 2009). AND PURPOSE Excess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this ‘proof-of-concept’ study, vascular function was characterized in the murine collagen-induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies. Levels of NO metabolites (NOx), MMP-9 protein and IL-1b in plasma and MMP-9 protein in aortic homogenates were quantified
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