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The Role of Activated Platelets in the Regulation of a Pro-Atherogenic Monocyte Phenotype

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thesis
posted on 17.07.2019, 09:09 by Sameer A. Kurmani
Platelets are circulating megakaryocytic fragments that have a well-established role in athero-thrombosis. Monocytes are circulating leucocytes which migrate to sites of endothelial damage, infiltrate a nascent plaque and avidly accumulate lipids to become foam cells. Evidence is provided to show that activated platelets accelerate this process by promoting a pro-atherogenic phenotype in monocytes and monocyte-derived monocytes (MDMs). A cross-linked collagen peptide mimetic (CRP-XL) was used to specifically activate platelets and monocytes were subsequently isolated and cultured using a methodology developed to minimise platelet contamination and iatrogenic activation. Activated platelets were shown to induce the formation of CD16pos monocytes from the previously CD16neg classical subset. This was accompanied by surface integrin (ICAM1, CD11b) and chemokine receptor expression (CXCR1, CXCR6) consistent with a pro-inflammatory phenotype. Platelets also induced the formation of intracellular lipid droplets in circulating monocytes and subsequently increased foam cells in MDMs which was dependent on the formation of monocyte-platelet aggregates (MPAs). This was shown to be as a result of both dysregulated cholesterol metabolism in MDMs and increased ingestion of platelets by monocytes. The in-vivo relevance of these findings were assessed in the FOAMI study, an observation, laboratory-based study of patients with non ST-elevation Myocardial Infarction (NSTEMI). Many of the in-vitro findings were recapitulated in patients within the first 24hrs of an MI, with increased intracellular lipid droplets, increased pro-inflammatory CD16pos monocyte subset and increased formation of foam cells above that seen in age-matched controls (AMC). Novel evidence is therefore provided to show that platelets induce a pro-atherogenic phenotype in monocytes and promote foam cell formation in MDMs. This has potentially important implications in the management of coronary artery disease (CAD) and might provide new therapeutic insights.

History

Supervisor(s)

Goodall, Alison

Date of award

14/06/2019

Author affiliation

Department of Cardiovascular Sciences

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

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