Date of Award

Winter 2018

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Diarmuid Smith

Second Supervisor

Dr Phil Cummins

Funder/Sponsor

Irish Endocrine Society

Keywords

Atherosclerosis, Cardiovascular Disease, Diabetes, Endothelium, Tnf Related Apoptosis Inducing Ligand, Oxidative Stress

Abstract

Background: Cardiovascular disease (CVD) remains the leading cause of death in patients with Type 2 diabetes mellitus (T2DM). Tumour necrosis factor related apoptosis inducing ligand (TRAIL) is a type II transmembrane protein that belongs to the tumour necrosis factor (TNF) superfamily. A growing body of clinical and animal studies highlight TRAILs vasoprotective potential, with TRAIL being linked to myocardial infarction and accelerated vascular calcification, whereas exogenous TRAIL administration exhibits anti-atherosclerotic activity. Throughout these studies, mechanistic information on the precise nature of TRAIL-mediated protection and the identity of the molecular/cellular targets of TRAIL is still extremely limited. The aims of this thesis were to characterise the effects of TRAIL on endothelial cells, as endothelial dysfunction is an important aspect of the atherosclerotic disease process, and to assess the suitability of TRAIL as marker of cardiovascular risk in patients with T2DM. Methods: We examined the effect of TRAIL on various end-points in human aortic endothelial cells (HAECs) in basal and injurious conditions. In tandem with our in vitro investigations, we compared serum TRAIL levels in non-diabetic controls, patients with T2DM and patients with T2DM and CVD. Results: TRAIL reduced oxidative stress in HAECs exposed to the pro-atherogenic conditions induced by oscillatory shear stress (OSS) and pro-inflammatory cytokines. Serum TRAIL was significantly lower in patients with T2DM and CVD compared to patients with T2DM alone or non-diabetic controls. TRAIL predicted the presence of CVD in patients with T2DM with adequate sensitivity and specificity. Conclusions: TRAILs vasoprotective effects in the vasculature are at least partly mediated by its ability to reduce oxidative stress. Pending further investigations in larger trials, serum TRAIL seems to be a useful diagnostic biomarker of clinically relevant CVD in patients with T2DM.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

3.37 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2018.

Available for download on Friday, May 15, 2020

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