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Identification of targets for the prognosis and/or treatment of vascular pathology associated with inflammatory arthritis.

Sime, Katherine 2018. Identification of targets for the prognosis and/or treatment of vascular pathology associated with inflammatory arthritis. PhD Thesis, Cardiff University.
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Abstract

Premature deaths in rheumatoid arthritis (RA) patients are linked to the development of cardiovascular pathologies. One mechanism that can influence vascular function during health and disease is mediators released from the perivascular adipose tissue (PVAT). However it is not known if PVAT morphology and/or function are altered during RA, contributing to the development of CVDs, or if this is a mechanism that can be therapeutically targeted. The collagen-induced arthritis (CIA) model was used to characterise alterations in PVAT morphology. An increase in total cell number and percentage macrophages in PVAT during CIA was accompanied by a decrease in adiposity. This thesis discovered that galectin-3 was specifically elevated in PVAT during arthritis and was subsequently selected as a PVAT-associated macrophage marker of vasculopathy during CIA. It is not known if elevated galectin-3 expression during inflammatory arthritis is associated with vascular dysfunction or if therapeutical intervention (e.g. with etanercept) affects galectin-3 expression. RA patients receiving etanercept have a reduced CV risk. Treatment with etanercept reduced the incidence of CIA and improved vascular function. Etanercept therapy reduced galectin-3 expression in PVAT during CIA but not systemically. Therefore the effect of direct galectin-3 inhibition on the vascular dysfunction associated with CIA was determined. Galectin-3 was inhibited in PVAT and in plasma by GB1107 during CIA. This novel therapy decreased the severity of CIA but did not prevent onset. Vascular function was partially restored in GB1107 treated mice, more so than in etanercept treated CIA mice. For the first time, this thesis showed that CIA altered PVAT morphology during CIA. Galectin-3 was highlighted as a marker of PVAT-associated vasculopathy, with inhibition of galectin-3 during CIA improving vascular function. Furthermore, this thesis demonstrated that CIA could be used as a platform to investigate the effects of therapeutic intervention on the associated vascular dysfunction that is linked to inflammatory arthritis.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 29 April 2019
Last Modified: 29 Apr 2019 13:18
URI: http://orca-mwe.cf.ac.uk/id/eprint/121975

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