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- W2488583717 abstract "The aim of my PhD thesis was to characterise the mechanism by which apolipoprotein E (apoE) inhibits agonist-induced platelet aggregation. Although pure apoE was inactive, apoE/phospholipid (apoE:DMPC) complexes induced a potent dose- dependent inhibition of platelet aggregation. This inhibition was abolished when platelets were pre-incubated with nitric oxide (NO) synthase inhibitors, implying that apoE stimulated NO production. Additionally, apoE:DMPC vesicles induced a marked dose- dependent increase in cGMP, indicating a stimulation of guanylate cyclase, the physiological target for NO. Confirmation that apoE stimulates NO synthase was obtained by use of an enzymatic assay; platelets pre-treated with apoE:DMPC produced four times more citrulline (the by-product of NO synthesis) than controls. The initial activating step was an apoE-receptor interaction. Chemically-modifying the arginine residues of apoE blocked the rise in platelet CGMP and the anti-aggregatory effect, while receptor associated protein (RAP), a potent inhibitor of apoE-receptor interactions, also prevented apoE's anti-platelet action. Finally, studies using synthetic peptides identified the active domain within the apoE molecule as the classical LDL receptor-binding domain (residues 142-145). Homology cloning was used to identify the platelet receptor. Sets of degenerate primers were used in RT-PCR to amplify the conserved binding domain of the LDL receptor super family from HEL cells (a megakaryocytic cell line). One PCR product matched apoE receptor 2 (apoER2), a newly described receptor confined mainly to the brain. Using a specific anti-peptide antiserum, apoER2 protein was detected in platelet membranes. Intriguingly, sequence analysis of cytoplasmic apoER2 identified a number of peptide motifs involved in tyrosine kinase signalling, implying this as the mechanism by which activated apoER2 and NO synthase are coupled. Since apoE and NO are both implicated in the pathology of atherosclerosis and Alzheimer's disease, the elucidation of the molecular mechanism by which apoE binding to apoER2 can activate platelet NO synthase may have widespread ramifications." @default.
- W2488583717 created "2016-08-23" @default.
- W2488583717 creator A5016732315 @default.
- W2488583717 date "1998-01-01" @default.
- W2488583717 modified "2023-09-22" @default.
- W2488583717 title "Inhibition of platelet aggregation by apolipoprotein E" @default.
- W2488583717 hasPublicationYear "1998" @default.
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