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Title: A role for phospholipase D in the response of human endothelial cells to vasoactive agents
Author: McHarg, Selina
ISNI:       0000 0001 3624 6780
Awarding Body: University of Exeter
Current Institution: University of Exeter
Date of Award: 2007
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Phospholipase D (PLD) is a ubiquitously expressed membrane associated enzyme. PLD has been shown to be activated by atherogenic lipids, mitogenic signalling pathways and is reported to be involved in chemotaxis. Thus it is frequently implicated in the ~evelopment of atherosclerosis. Development of vascular disease is strongly associated with type II diabetes, and it is widely thought that endothelial dysfunction is one of the initiating factors in the development of this vascular disease. Interestingly, PLD has been shown to be activated by factors prevalent in type II diabetes such as hyperglycaemia and reactive oxygen species, raising the possibility that PLD activation may playa role in endothelial dysfunction. The aim of this project was to investigate whether PLD is activated by vasoactive agents known to contribute to vascular dysfunction in type II diabetes in human macrovascular and microvascular endothelial cells. The results presented demonstrate that PLD is significantly activated by 1nM insulin in both macrovascular and microvascular endothelial cells, and this activation appears to be downstream of PI3K and ERK1/2 activation. During this activation there appears to be increased co-localisation of the insulin receptor-J3 subunit with PLD and the caveolae. Furthermore, chronic exposure to hyperinsulinemia enhances basal PLD activation, but abolishes its responsiveness to acute exposures of 1 nM insulin. Translocation of Art and PKCa - classic regulators of PLD - do not appear to be involved in this enhanced activation. This study also demonstrates that other factors known to be involved in vascular dysfundion in type II diabetes such as the proatherogenic lipid lysophosphatidylcholine and angiotensin II significantly activate PLD in micro and macrovascular endothelial cells, though there appears to be differential activation of PLD with respect to cell type. In summary, the observed activation of PLD by insulin in endothelial cells is a novel finding, this combined with its enhanced activation by hyperinsulinemia and other vasoactive agents known to elicit vascular dysfunction strongly implicates a role for PLD in endothelial cell signalling in the type II diabetic environment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available