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Characterisation of microparticles and nitro-oxidative stress in cardiometabolic disease

Willis, Gareth 2015. Characterisation of microparticles and nitro-oxidative stress in cardiometabolic disease. PhD Thesis, Cardiff University.
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Polycystic ovary syndrome (PCOS) is a common condition characterised by hyperandrogenism, oligo/anovulation and defects in insulin secretion and sensitivity. PCOS patients also have an increased prevalence of hypertension, dyslipidaemia and endothelial dysfunction, a state associated with decreased nitric oxide bioavailability and increased oxidative stress. Using women with PCOS as a model of predisposition to cardiovascular disease (CVD), the aim of this thesis was to provide a clearer understanding of mechanisms that may predispose individuals to endothelial dysfunction, and ultimately CVD. PCOS patients were compared to healthy controls in an observational study, which involved a comprehensive assessment of biochemical nitro-oxidative stress indices and a detailed characterisation of circulating microparticles (MPs). There was little evidence to suggest that women with PCOS have an increased oxidative stress compared to age/BMI-matched controls. However, PCOS patients did display elevated levels of annexin V positive MPs that were predominantly derived from platelets. In vitro studies investigated the effect of several metabolic stressors akin to those found in PCOS on endothelial-derived MP characteristics and function. Human endothelial (HECV) cells were exposed to oxidative, hypoxic, hyperandrogenic and metabolic stressors. Each metabolic stressor affected MP generation uniquely, suggesting MP characteristics and function reflect parental cell conditions. In order to determine whether circulating MP levels could be modulated in a clinical cohort, the effect of apheresis on circulating MP levels was investigated in patients with established CVD (familial hypercholesterolaemia). Apheresis decreased circulating levels of MPs and was associated with a decreased thrombin generation capacity in these patients. The data in this thesis thus provide evidence that young women with PCOS have an elevated concentration of annexin V positive MPs, even though there is little biochemical evidence for nitro-oxidative stress. Further studies are needed to assess the effect of this increase in circulating MPs on cardiovascular clinical end-points. In vitro experiments showed that the cellular stress condition is reflected in the MP characteristics, whereby each pathological stressor resulted in a unique MP phenotype. Furthermore, in patients with established CVD, apheresis reduced circulating levels of MPs. In conclusion, an elevated annexin V positive MP population may represent a novel mechanism by which cardiovascular risk is increased in patients with PCOS. These findings could have future implications for use as biomarkers, in diagnosis and therapeutics.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Funders: Mrs John Nixon Scholarship
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:54

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