Anti-inflammatory effects of anti-platelet drugs : implications for atherosclerosis

• Main Author: Layne, Kerry Anne
• Other Authors: Passacquale, Gabriella ; Ferro, Albert
• Published: King's College London (University of London) 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.739993

Cardiovascular disease secondary to atherosclerosis is the leading cause of death worldwide. The pathophysiology of atherosclerosis is multifactorial and complex. This thesis offers insight into the regulation of several potential biomarkers of cardiovascular disease and explores the effects of anti-platelet therapy in modulating these pathways. CD14highCD16+ monocytes are elevated in patients with atherosclerosis and may be predictive of future cardiovascular events. The initial study in this PhD project assessed the effects of anti-platelet drugs on the phenotype of circulating monocytes in 60 healthy volunteers in the presence of mild, systemic inflammation induced by the influenza immunisation. A significant rise in circulating CD14highCD16+ monocytes developed following immunisation and anti-platelet therapy was subsequently shown to exert an immunomodulatory action by counteracting this response. Netrin-1 is a laminin-like protein that is implicated in cardiovascular disease, including coronary artery disease. A series of experiments were performed to investigate the biomolecular mechanisms that regulate the synthesis of vascular netrin-1 in humans. Results showed that netrin-1 levels are directly modulated by changes in the production of vasoactive cyclooxygenase-derived molecules, such as prostaglandin E2, from the vascular endothelium. Oxidised low-density lipoprotein was the final biomarker that was investigated. Results indicated that CD16+ monocytes may regulate the clearance of oxidised lipoproteins and their systemic accumulation, possibly through the internalisation of circulating oxLDL/IgG immunocomplexes mediated by Fc γ receptors, including CD16.