title: Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase-9.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 (NO(x)), MMP-9 protein and IL-1β in plasma and MMP-9 protein in aortic homogenates were quantified.
  
  
  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 NO(x) 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
  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.
authors.affiliation: Wales Heart Research Institute, School of Medicine, Cardiff University, Heath Park Campus, Cardiff, UK.
authors.forename: S l
authors.initials: Sl
authors.lastname: Reynolds
authors.forename: A S
authors.initials: AS
authors.lastname: Williams
authors.forename: H
authors.initials: H
authors.lastname: Williams
authors.forename: S
authors.initials: S
authors.lastname: Smale
authors.forename: H J
authors.initials: HJ
authors.lastname: Stephenson
authors.forename: N
authors.initials: N
authors.lastname: Amos
authors.forename: S J
authors.initials: SJ
authors.lastname: George
authors.forename: V B
authors.initials: VB
authors.lastname: O'Donnell
authors.forename: D
authors.initials: D
authors.lastname: Lang
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000150:complications / Q000503:physiopathology*; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009213:Myography; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D020780:Matrix Metalloproteinase 9