Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase-9

Reynolds, Sophie Leanne, Williams, Anwen Sian ORCID: https://orcid.org/0000-0001-6118-020X, Williams, H., Smale, Shaun, Stephenson, Hayden J., Amos, Nick, George, S. J., O'Donnell, Valerie Bridget ORCID: https://orcid.org/0000-0003-4089-8460 and Lang, Derek 2012. Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase-9. British Journal of Pharmacology 167 (3) , pp. 505-514. 10.1111/j.1476-5381.2012.01988.x

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Abstract

BACKGROUND 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. EXPERIMENTAL APPROACH Mice 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 RESULTS Impaired 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 IMPLICATIONS These 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	arthritis, cardiovascular disease, aorta, contractile dysfunction, matrix metalloproteinase 9
Publisher:	Nature Publishing Group
ISSN:	0007-1188
Last Modified:	24 Oct 2022 09:48
URI:	https://orca.cardiff.ac.uk/id/eprint/42168

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