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
Redefining The Role Of Macrophages In Atherosclerosis: Macrophage Subset Role In Plaque Stability
Funder
National Health and Medical Research Council
Funding Amount
$509,190.00
Summary
Vascular disease is a major cause of death and disability through events such as heart attack and stroke. A blood cell, called a macrophage, plays a major detrimental role. However, we have identified the presence of an alternate form of this cell in vascular disease that we propose may play an opposing, beneficial role. We will thus re-define the role of the macrophage in vascular disease and predict that we will be able to demonstrate an alternate healing role. This will provide a new therapeu ....Vascular disease is a major cause of death and disability through events such as heart attack and stroke. A blood cell, called a macrophage, plays a major detrimental role. However, we have identified the presence of an alternate form of this cell in vascular disease that we propose may play an opposing, beneficial role. We will thus re-define the role of the macrophage in vascular disease and predict that we will be able to demonstrate an alternate healing role. This will provide a new therapeutic approach for treatment of atherosclerosis.Read moreRead less
Preventing Myocardial Infarction: A Mouse Model Of Atherosclerotic Plaque Instability/rupture As Unique Tool For Establishing Novel Pharmacological Strategies And Targeted Molecular Imaging
Funder
National Health and Medical Research Council
Funding Amount
$586,965.00
Summary
Myocardial infarction strikes without warning and thereby causes death or major disability. It is typically caused by sudden rupture of atherosclerotic plaques and occlusion of coronary arteries. Research on this was hampered by the lack of an animal model of plaque rupture. We have newly established a mouse model, which we will now use to generate novel tools to image and identify plaques that are prone to rupture and to develop novel therapies preventing plaque rupture and myocardial infarctio ....Myocardial infarction strikes without warning and thereby causes death or major disability. It is typically caused by sudden rupture of atherosclerotic plaques and occlusion of coronary arteries. Research on this was hampered by the lack of an animal model of plaque rupture. We have newly established a mouse model, which we will now use to generate novel tools to image and identify plaques that are prone to rupture and to develop novel therapies preventing plaque rupture and myocardial infarction.Read moreRead less
The Role Of TRAIL And TRAIL Receptors In Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$563,838.00
Summary
The death factor, TNF-related apoptosis inducing ligand (TRAIL) is implicated in the development of atherosclerosis and can regulate cell death in the vessel wall. Recent conflicting roles for TRAIL have been described. Surprisingly, TRAIL can also stimulate cell growth. Using mice lacking TRAIL, this study will establish the function of TRAIL in models of (i) injury to the artery wall and (ii) an atherosclerotic plaque. This study will also initiate a new area of research in Australia.
Angiopoietin-2, Aortic Inflammation And Cardiovascular Events
Funder
National Health and Medical Research Council
Funding Amount
$332,161.00
Summary
Based on detailed preliminary data, we plan to investigate the importance of a novel protein (the cytokine angiopoietin-2) in cardiovascular disease. The results of this study will clarify the role of this cytokine in vascular pathology and may provide an important target for novel therapy and-or diagnostic markers for cardiovascular disease progression.