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Characterisation of vascular dysfunction in a murine model of rheumatoid arthritis

Williams, Jessica 2016. Characterisation of vascular dysfunction in a murine model of rheumatoid arthritis. PhD Thesis, Cardiff University.
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Background RA patients have an increased prevalence of CVD independently of traditional risk factors. Studies using a mouse model of inflammatory arthritis – mCIA have shown decreased vascular constriction response of the thoracic aorta to 5HT, associated with increased MMP-9 production. The source of the latter, inflammatory content and impact on the structural proteins of the vessel wall remains elusive. Methods Myography was used to determine vascular constriction response in mCIA animals. Immunohistochemistry determined presence of F4/80+ macrophages, Ly6G+ neutrophils, DR3 and MMP-9. DR3 was assessed in the healthy and arthritic constriction response using DR3-/- and DR3WTs. Vascular calcification was determined in short and long term mCIA using RT-qPCR. Protein levels were quantified using immunohistochemistry. Collagen and elastin were determined using Van Geisson and Ver Hoeffs staining. The role of the AIM2 inflammasome in mCIA associated vascular dysfunction was also determined using CRID3 therapy. Results Increased macrophages with complimentary DR3 staining were observed in the aorta and PVAT.DR3-/- had normal constriction response despite increased cells and MMP-9 in the PVAT. DR3 ablation decreased arthritis onset and severity, however, worsened the vascular function. DR3 PVAT was protective to the constriction response. Calcification mediators remained constant following the onset of mCIA. Long term mCIA showed exciting trends of increase to calcification mediators. Collagen and elastin both become deregulated during mCIA and showed a fibrosis like phenotype. Blocking the AIM2 inflammasome had no impact on mCIA onset but partially restored vascular constriction response. Discussion Systemic inflammation is key in explaining the vascular dysfunction associated with the mCIA model. mCIA allows us to determine very early changes in the vasculature associated with systemic inflammation as opposed to long term changes. Macrophages specifically are early inflammatory cells implicated in the aorta and are associated with both DR3 and AIM2, suggesting them as key players contributing to vascular dysfunction in this model. Successful AIM2 blocking therapy has potential to be used in human RA patients to reduce CV co-morbidity.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Date of First Compliant Deposit: 10 April 2017
Last Modified: 04 Jun 2017 09:47

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