Molecular Mediators of Macrophage Foam Cell Formation and Atherosclerosis and their Pharmacological Modification
type: CreativeWork
description: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death and morbidity around the world. It results from build-up of cholesterol-rich, inflamed plaques in the walls of arteries. Inflammation is central to atherosclerosis. A key driver of inflammation in plaque is the accumulation of cholesterol-laden macrophages, called foam cells. Uncontrolled inflammation in plaques makes them “unstable” and vulnerable to rupture and thrombosis, which causes complications, such as myocardial infarction (MI) in the case of atherosclerotic coronary artery disease (CAD). Current therapies, such as lipid-lowering statins, do not adequately control plaque inflammation, leaving an unacceptably high residual risk of adverse cardiovascular events in patients with subclinical and clinical ASCVD. Consequently, new anti-atherosclerotic therapies are needed, especially those that can better target plaque inflammation. This thesis set out to mechanistically investigate the regulation of macrophage functions in the context of atherosclerosis using two therapeutic approaches: (1) the repurposing of the well-established, anti-gout drug, colchicine; and (2) the genetic knock-out and pharmacological inhibition of eukaryotic elongation factor 2 kinase (eEF2K), a structurally unique enzyme known to be important for protein translation in cells under different stress conditions. Colchicine is a broad-acting anti-inflammatory agent that has attracted considerable interest for repurposing in ASCVD. Despite evidence for outcome benefits in stable CAD and after recent MI, the mechanistic basis for colchicine’s actions in ASCVD remains speculative and poorly defined. Chapter 3 of this thesis aimed to dive deep into colchicine's actions on one of the key immune cells involved in atherosclerosis, namely macrophages. This in vitro and ex vivo body of work was supported by collaborative in vivo studies, which explored whether colchicine reduces plaque burden and stabilises plaque composition …
abstract: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death and morbidity around the world. It results from build-up of cholesterol-rich, inflamed plaques in the walls of arteries. Inflammation is central to atherosclerosis. A key driver of inflammation in plaque is the accumulation of cholesterol-laden macrophages, called foam cells. Uncontrolled inflammation in plaques makes them “unstable” and vulnerable to rupture and thrombosis, which causes complications, such as myocardial infarction (MI) in the case of atherosclerotic coronary artery disease (CAD). Current therapies, such as lipid-lowering statins, do not adequately control plaque inflammation, leaving an unacceptably high residual risk of adverse cardiovascular events in patients with subclinical and clinical ASCVD. Consequently, new anti-atherosclerotic therapies are needed, especially those that can better target plaque inflammation. This thesis set out to mechanistically investigate the regulation of macrophage functions in the context of atherosclerosis using two therapeutic approaches: (1) the repurposing of the well-established, anti-gout drug, colchicine; and (2) the genetic knock-out and pharmacological inhibition of eukaryotic elongation factor 2 kinase (eEF2K), a structurally unique enzyme known to be important for protein translation in cells under different stress conditions. Colchicine is a broad-acting anti-inflammatory agent that has attracted considerable interest for repurposing in ASCVD. Despite evidence for outcome benefits in stable CAD and after recent MI, the mechanistic basis for colchicine’s actions in ASCVD remains speculative and poorly defined. Chapter 3 of this thesis aimed to dive deep into colchicine's actions on one of the key immune cells involved in atherosclerosis, namely macrophages. This in vitro and ex vivo body of work was supported by collaborative in vivo studies, which explored whether colchicine reduces plaque burden and stabilises plaque composition …
author: Fernando, Weerahennedige Sanuja Lakshani
language: en
keywords: Atherosclerosis, plaque, macrophages, foam cells, eEF2K, colchicine, cardiovascular
date published: 2020
date modified: 2026-07-24T00:50:56Z
provider: University of Adelaide
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Adelaide

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2440/130122