The influence of oxidised low density lipoproteins on platelet activation
Wraith, Katie Suzanne
Thesis or dissertation
- © 2013 Katie Suzanne Wraith. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
The oxidation of low density lipoproteins (LDL) may contribute to platelet hyperactivity and thrombotic events in cardiovascular diseases. Although these pathological particles are known to stimulate platelet activation, the exact signalling mechanisms involved are poorly defined. The aim of this study was to explore the mechanisms underpinning platelet activation by oxidised LDL (oxLDL). OxLDL but not native LDL (nLDL) induced a modest degree of aggregation, which was ADP dependent. However, oxLDL was able to induce shape change, one of the earliest stages of platelet activation, independently of secondary agonists. Platelet shape change requires the protein myosin, the activity of which is controlled by the phosphorylation of its regulatory light chains (MLC) at serine¹⁹. Physiological platelet agonists activating platelets through G protein coupled receptors stimulate MLCSer¹⁹ phosphorylation by the activation of dual pathways that lead to a Ca²⁺ dependent activation of MLC kinase (MLCK) and the Rho kinase dependent inhibition of MLC phosphatase (MLCP). OxLDL induced platelet shape change correlated with MLCSer¹⁹ phosphorylation. OxLDL also stimulated a tyrosine kinase pathway involving the proteins Syk and PLCγ2, which were confirmed to be involved in MLCSer¹⁹ phosphorylation. Furthermore, oxLDL triggered a second pathway involving the activation of RhoA leading to the activation of Rho kinase and subsequent inhibition of MLCP. A receptor that has been continuously linked to oxLDL induced platelet activation is the scavenger receptor CD36. The expression of this scavenger receptor was found to increase upon stimulation with a range of platelet agonists. Furthermore, platelet shape change was discovered to be downstream of CD36. The findings of this report therefore elucidate two novel signalling pathways in response to CD36 ligation with oxLDL. Enhancements in understanding how this pathological ligand can contribute to platelet activation may lead to improvements in the treatments available for patients who suffer with hyperlipidaemia and cardiovascular diseases.
- Hull York Medical School, The University of Hull
- Naseem, Khalid
- Qualification level
- Qualification name
- 6 MB