Damage to arterial extracellular matrix induced by reactive nitrogen species and its consequences

Funded Activity 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 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.

Funded Activity Details

Start Date: 01-01-2005

End Date: 01-01-2007

Funding Scheme: NHMRC Project Grants

Funding Amount: $326,250.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Cardiology (incl. Cardiovascular Diseases)

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

Atherosclerosis | Atherosclerotic plaque rupture | Cardiovascular sequalae | Extracellular matrix | Glycosoaminoglycans | Oxidative Stress | Peroxynitrite | Plaque rupture | Protein oxidation

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