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The influence of lipoproteins and peroxides on platelet activation and inhibition

Naseem, Khalid Malik; (1996) The influence of lipoproteins and peroxides on platelet activation and inhibition. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Low density lipoproteins (LDL) have been implicated as possible pro-thrombotic factors by enhancing platelet responsiveness. The aim of this study was to assess how the degree of oxidative modification of LDL altered their effects on platelet function. The effects of native and modified LDL on platelet responsiveness and platelet sensitivity to nitric oxide (NO) in vitro were assessed by conventional aggregometry and flow cytometry combined with immunolabelling. Native LDL (nLDL) inhibited activation in platelet rich plasma (PRP) and aggregation of washed platelets (WP). Oxidised LDL (oxLDL) also inhibited platelet activation in PRP, but was found to inhibit aggregation in both PRP and WP, suggesting that inhibition was induced by a different mechanism to that of nLDL. In contrast, minimally modified LDL (mmLDL) potentiated ADP-induced fibrinogen binding and aggregation, possibly by enhanced release of platelet granules, and induced primary aggregation of WP independently of other agonists. The major physicochemical difference between native and minimally modified LDL was a relatively small increase in the level of lipid hydroperoxides (LPO), these low levels of LPO may account for the contrasting effects of nLDL and mmLDL with respect to platelet function. The data suggest that mmLDL may be potentially important pro-thrombotic factors. The influence of peroxides on platelet aggregation and the sensitivity of platelets to NO were investigated using hydrogen peroxide, cumene hydroperoxide and 15 (S)-hydroperoxyeicosatetraenoic acid as models for LPO. Hydrogen peroxide, and cumene hydroperoxide both potentiated agonist-1 induced aggregation, but only when added post-agonist. These peroxides also attenuated the inhibition of platelet aggregation by NO when added postagonist. 15 (S)-hydroperoxyeicosatetraenoic acid alone did not affect aggregation, but potentiated aggregation when used as a complex with nLDL. 15 (S)-hydroperoxyeicosatetraenoic acid antagonised the inhibitory actions of NO, but this only occurred when the peroxide was incubated with platelets before the addition of NO and thrombin. In contrast, if hydrogen peroxide and NO were added to platelets before thrombin, aggregation was inhibited to a greater extent than by NO alone. The presence of hydrogen peroxide prolonged and enhanced the effects of NO when applied directly to WP. This was due in part to increased stimulation of guanylate cyclase activity, and could be reproduced with an NO-donor. Simultaneous addition of NO with cumene hydroperoxide or 15 (8)- hydroperoxyeicosatetraenoic acid did not produce the same effect. This suggested that hydrogen peroxide may have a physiological role in the enhancement of inhibition of platelets by NO.

Type: Thesis (Doctoral)
Title: The influence of lipoproteins and peroxides on platelet activation and inhibition
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: http://discovery.ucl.ac.uk/id/eprint/1566742
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