Connexin 43 as a biological marker of ischaemia in occlusive arterial disease of the lower limb

Hussey, Keith Kelso (2018) Connexin 43 as a biological marker of ischaemia in occlusive arterial disease of the lower limb. MD thesis, University of Glasgow.

Abstract

Diabetes mellitus is a worldwide health issue. It is a major and growing cause of morbidity and mortality. Rates of end-organ damage are increasing proportionately, as are the associated personal, societal and economic costs. Diabetic foot ulceration is responsible for a significant proportion of this. The development of diabetic foot ulceration is complex with multiple injurious processes potentially affecting a foot at any time. Defining the significance of ischaemia as a consequence of peripheral arterial occlusive disease can be difficult and identifying which patients may benefit from revascularisation in terms of reversing of the natural history of the disease process remains poorly understood.

The utility of the University of Texas classification to identify patients at highest risk of major adverse clinical events has been explored from 971 ulcer episodes affecting 515 limbs (388 patients). Peripheral arterial occlusive disease was identified in 44.6%. These patients had a significantly higher risk of major amputation than patients without peripheral arterial occlusive disease (13.5 versus 4%). University of Texas scoring would appear to robustly identify patients at highest risk of major adverse clinical events.

The potential usefulness of Connexin 43 and its phosphorylated isoform Connexin 43(Serine368) as biological markers of ischaemia in skin have been explored. Immunohistochemistry provided qualitative data demonstrating up regulation of Connexin 43(Serine368) in skin biopsies from ischaemic feet – this is a novel finding. Connexin 43 (Serine368) was not identified in any of the controls nor in proximal skin biopsies of patients with peripheral arterial occlusive disease. Connexin 43 expression did not appear to be modified.

When human fibroblasts and keratinocytes were subjected to hypoxic conditions (1% oxygen/4% carbon dioxide/nitrogen) in vitro, both Connexin 43 and Connexin 43(Serine368) were up regulated with protein expression peaking between 12 to 24 and 6 to 12 hours respectively. Peptidoglycan challenge appeared to up-regulate the expression of Connexin 43 protein, but did not influence the expression of Connexin 43(Serine368). These data suggest that Connexin 43(Serine 368) may have potential utility as a biological marker of ischaemia in human skin

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Keywords: Diabetes mellitus, Critical limb ischaemia, Atherosclerotic arterial disease, Connexin 43.
• Subjects: R Medicine > RD Surgery
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Horgan, Professor Paul
• Date of Award: 2018
• Depositing User: Mr Keith Hussey
• Unique ID: glathesis:2018-30744
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 21 Aug 2018 08:37
• Last Modified: 21 Aug 2018 08:51
• URI: https://theses.gla.ac.uk/id/eprint/30744