Damage To Arterial Extracellular Matrix Induced By Reactive Nitrogen Species And Its Consequences
Funder
National Health and Medical Research Council
Funding Amount
$326,250.00
Summary
It is well established that lipids accumulate in the artery wall during the development of atherosclerosis (hardening of the arteries), and that much of this lipid arises from low-density lipoproteins (LDL). The uptake of cholesterol and lipids from LDL by cells present in the arterial wall is normally tightly regulated and under feedback control, but modification of the LDL particles can result in their recognition by the scavenger receptors of macrophage cells and unregulated accumulation of l ....It is well established that lipids accumulate in the artery wall during the development of atherosclerosis (hardening of the arteries), and that much of this lipid arises from low-density lipoproteins (LDL). The uptake of cholesterol and lipids from LDL by cells present in the arterial wall is normally tightly regulated and under feedback control, but modification of the LDL particles can result in their recognition by the scavenger receptors of macrophage cells and unregulated accumulation of lipids within such cells. The formation of these lipid-laden (foam) cells is a hallmark of atherosclerosis. Whilst this lipid accumulation is undesirable, if the resulting lesions are stable they are of less concern than those that are unstable and prone to rupture. Rupture of lesions and consequent blood clot formation (thrombosis) are a prime cause of sudden heart death and stroke. Despite considerable effort the reasons for plaque rupture are poorly understood. This study will investigate one potential mechanism by which lesions might become destabilised and prone to rupture. We will investigate the role of reactive intermediates in inducing damage to the extracellular matrix. Reactive intermediates are known to be generated by inflammatory cells, and it is well established that these cells are present at elevated levels in lesions. The extracellular matrix is responsible for maintaining the 3-dimensional structure of biological systems including the artery wall, and damage or fragmentation of this material may weaken this scaffolding and make the lesions prone to rupture. We will also examine how such matrix damage affects the behaviour of cells within lesions. A detailed knowledge of which processes are important in lesion rupture is an essential prerequisite to the development of new therapeutic strategies.Read moreRead less
Myeloperoxidase-catalysed Damage To Arterial Extracellular Matrix And Its Consequences
Funder
National Health and Medical Research Council
Funding Amount
$384,750.00
Summary
A heme enzyme (myeloperoxidase) has been shown to be present in the lesions present in diseased human arteries, and it has been reported that this enzyme contributes to the development of arterial disease via its ability to catalyse the formation of highly reactive oxidants. Recent studies have shown that the level of this enzyme correlate strongly with the presence of coronary artery disease, and that this enzyme may play a role in plaque rupture, a leading cause of sudden coronary death. It ha ....A heme enzyme (myeloperoxidase) has been shown to be present in the lesions present in diseased human arteries, and it has been reported that this enzyme contributes to the development of arterial disease via its ability to catalyse the formation of highly reactive oxidants. Recent studies have shown that the level of this enzyme correlate strongly with the presence of coronary artery disease, and that this enzyme may play a role in plaque rupture, a leading cause of sudden coronary death. It has also been reported that elevated levels of metal ions are present in advanced human atherosclerotic lesions. In recent experiments we have shown that products generated by myeloperoxidase can interact with metal ions and superoxide radicals, and that this process results in an exacerbation of damage. This synergism between the oxidants generated by myeloperoxidase and metal ions may explain, at least in part, the complex mixture of products detected in human lesions and be responsible for the weakening of lesion structure and contribute to an enhanced likelihood of plaque rupture. This study will examine the potential effects and mechanisms of damage to extracellular matrix materials from normal arteries and cultured cells We will examine under what circumstances interactions occur and whether these reactions may play a key role in plaque rupture. We will also examine how materials arising from damage to the extracellular matrix may affect the cells whic grow upon this scaffolding, and whether this may be partly responsible for altered behaviour of cells within dveloping atherosclerotic lesions. A detailed knowledge of which processes are important in plaque rupture is an essential pre-requisite to the development of new therapeutic strategies.Read moreRead less
Serial Imaging Of Molecular And Microstructural Changes In Atherosclerosis: Tracking Plaques Towards Destabilisation
Funder
National Health and Medical Research Council
Funding Amount
$992,112.00
Summary
Most heart attacks are caused by high-risk plaques in coronary arteries. A significant unmet need in cardiology is to reliably detect high-risk plaques before they are life-threatening. This project will generate unique insights into plaque pathogenesis over time to see how plaques become high-risk and cause heart attacks. This project will also develop a clinically applicable tool to detect high-risk plaques, leading to significantly reduced complications and cost in heart disease.
Systems Biology To Identify Molecular Targets For Vascular Disease Treatment (SysVasc), With A Focus On Atherosclerotic Plaque Instability
Funder
National Health and Medical Research Council
Funding Amount
$450,721.00
Summary
Heart attacks are caused by rupture of atherosclerotic deposits (plaques) in vessel walls, which results in clot formation ultimately causing vessel occlusion. In collaboration with strong European collaborators, we will use modern high-throughput technologies in a large patient cohort as well as in a newly generated mouse model to discover the causative proteins, genes and their regulators. This will allow identifying individuals at risk and developing novel therapies to prevent heart attacks.
Potential Novel Pharmacological Strategies To Prevent Atherosclerotic Plaque Rupture
Funder
National Health and Medical Research Council
Funding Amount
$1,584,568.00
Summary
Most heart attacks are the consequence of the acute rupture of plaques in arteries that supply our heart with oxygen and nutrients. Current standard tests cannot distinguish plaques that likely rupture from plaques that do not rupture. Similarly, little is known about the processes that determine whether a plaque is vulnerable to rupture or stable. The current project examines the involvement of two processes - either alone or in combination - in determining plaque stability/vulnerability.
The Unstable, Rupture-prone Atherosclerotic Plaque: Innovative Methods For Its Detection And Stabilisation
Funder
National Health and Medical Research Council
Funding Amount
$748,447.00
Summary
Heart attacks and strokes are most often caused by rupture of unstable atherosclerotic plaques resulting in clotting and vessel occlusion and ultimately irreversible damage of the heart or brain. We have generated a mouse model that reproduces these plaques as seen in humans. Based on this model and human unstable plaques 1) we have discovered/developed imaging technologies that can identify these dangerous plaques and 2) we will develop drugs that prevent plaque rupture.
Urine Proteomics As A New Diagnostic Approach For Cardiovascular Risk And As A Discovery Tool For Novel Pathomechanisms In Atherosclerotic Disease
Funder
National Health and Medical Research Council
Funding Amount
$69,500.00
Summary
Atherosclerosis (hardening of blood vessels) followed by blockage is the leading cause of death due to heart attacks and strokes. Up until now there has been no simple tests to predict this reliably.The outcome of this project will give us a better understanding of atherosclerosis and provide a simple non-invasive urine test to detect atherosclerosis which would lend clinicians the opportunity to intervene early.
Development Of A Catheter-based Device For The Detection Of Vulnerable Atherosclerotic Plaques
Funder
National Health and Medical Research Council
Funding Amount
$560,582.00
Summary
Atherosclerosis (hardening of blood vessels) is a major cause of disability and death worldwide. These lesions can suddenly become unstable leading to rupture and the occlusion of blood vessels with catastrophic complications such as heart attacks and strokes. Our project aims to develop a novel invasive imaging system to reliably detect these unstable lesions before they cause complications so that preventive measures can be taken, potentially saving many lives.
A Study Of The Plaque-modifying Actions Of Colchicine In Stable And Unstable Atherosclerosis: From Mouse Models To Clinical Imaging.
Funder
National Health and Medical Research Council
Funding Amount
$1,198,460.00
Summary
Inflammation causes the plaques in arteries that cause heart attacks and strokes. There is major interest in developing drugs that reduce this inflammation for patients with heart disease. We are studying the effects of colchicine, an anti-inflammatory drug used to treat the joint disease, gout, in order to see whether it also prevents the build up of plaques and their progression to heart attacks and strokes.