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The effect of inorganic nitrate and nitrite on the production and function of extracellular vesicles

Burnley-Hall, Nicholas 2017. The effect of inorganic nitrate and nitrite on the production and function of extracellular vesicles. PhD Thesis, Cardiff University.
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Extracellular vesicles (EVs) are spherical, submicron particles enclosed in a phospholipid bilayer, shown to have pathophysiological roles in a plethora of disease states, including cardiovascular disease (CVD). The development of an atherosclerotic plaque can lead to downstream hypoxia, which is known to stimulate the production of EVs. Nitric oxide (NO) plays a pivotal role in vascular homeostasis, highlighted by the deficiency of NO in CVD states. The inorganic anions nitrate (NO3-) and nitrite (NO2-) represent bioactive reservoirs of NO, particularly under hypoxic conditions. Therefore, the aim of this thesis was to explore the effect of inorganic NO3-/ NO2- on the production and function of EVs in CVD. In vitro, hypoxia-inducible factor-1α (HIF-1α) was shown to mediate hypoxic EV release in endothelial cells. Furthermore, NO2- derived NO increased HIF-1α degradation, and subsequently reduced EV production. This effect was attenuated by inhibition of xanthine oxidoreductase, preventing NO2- conversion to NO. Following this, hypoxic endothelial-derived EVs were shown to enhance pro-coagulant and pro-inflammatory responses in comparison to EVs derived from normoxia. Treatment of hypoxic cells with NO2- reversed the pro-coagulant effects of the EVs produced, but did not alter their effect on inflammation. In order to determine whether modulation of EV production was also possible in vivo, healthy volunteers were given a dietary NO3- supplement daily for 6 days. However, there was no change in circulating EVs over the course of this treatment. Finally, a NO3- supplement was given to CVD patients, which significantly reduced circulating EVs only in patients on clopidogrel, suggesting the formation of a thienopyridine-nitrosothiol derivative. In conclusion, the NO metabolites NO3- and NO2- appear capable of reducing the production of pathogenic EVs, representing a novel therapeutic approach which may be of interest in the future treatment of CVD.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 9 January 2018
Last Modified: 19 Oct 2019 02:33

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