The role of scavenger receptors in oxidised low-density lipoprotein induced platelet hyperactivity

Woodward, Casey

Abstract

Increased platelet hyperactivity is a common consequence of hyperlipidemia and is associated with increased risk of acute coronary syndromes. Platelet interaction with oxidised low-density lipoprotein (oxLDL) is believed to play a crucial role in platelet hyperactivity, although the mechanisms underpinning this are poorly understood. The aims of this study was to further understand the effects of oxLDL on platelet function. We performed a detailed characterisation of the conditions of LDL oxidation that generated a biologically active group of particles. Using this LDL preparation we show that oxLDL caused platelet degranulation, shape change and aggregation. This occurred through ligation to the receptor CD36, shown via pharmaceutical and knockout mouse data, with other evidence suggesting a supporting role for lectin-like oxidised LDL receptor 1 (LOX- 1). OxLDL promoted adhesion to collagen, but not fibrinogen in human platelets, which was lost in murine platelets deficient in CD36. Interestingly, we found that whilst oxLDL did not promote thrombus formation on collagen, it reduced the effects of both cyclic guanosine monophosphate and cyclic adenosine signaling pathways on platelet thrombus formation. We next examined the mechanisms underpinning ability of oxLDL to alter platelet function. Using immunoblotting, we found a central role for tyrosine kinase signaling in oxLDL mediated activation of platelets. We showed inactivation of Src family kinases, spleen tyrosine kinase (Syk), phospholipase Cγ2 (PLCγ2) and phosphoinositide 3- kinase (PI3-K), using a range of established pharmaceutical inhibitors, prevented platelet spreading to oxLDL. We later focused on PLCγ2 in greater detail, showing the protein to be tyrosine phosphorylated in platelets in response to oxLDL. We attempted to confirm these results in PLCγ2 deficient mice, although these mice showed no altered response to the oxidised lipid KOdiA-PC, requiring further investigation. The findings of this report support previous findings of a tyrosine kinase dependent signalling pathway and offer novel insight into how oxLDL is able to affect platelet reactivity by modulation of the effects of endogenous inhibitors. In summary, this data could suggest that the primary effect of oxLDL is to change the balance between platelet activatory and inhibitory pathways and therefore reduce the threshold for platelet activation.

[Thesis also includes article published in Blood journal: http://www.bloodjournal.org/content/125/17/2693
DOI: 10.1182/blood-2014-05-574491]

Citation

Woodward, C. (2016). The role of scavenger receptors in oxidised low-density lipoprotein induced platelet hyperactivity. (Thesis). Hull York Medical School, the University of Hull and the University of York. Retrieved from https://hull-repository.worktribe.com/output/4218666

• Thesis Type: Thesis
• Deposit Date: Nov 8, 2016
• Publicly Available Date: Feb 23, 2023
• Keywords: Medicine
• Public URL: https://hull-repository.worktribe.com/output/4218666
• Additional Information: Hull York Medical School, The University of Hull and the University of York
• Award Date: Aug 1, 2016