Pathogenesis and treatment of cholesterol-related early vascular injury

This thesis describes studies into the pathogenesis of Cholesterol—related early vascular injury. In addition, this thesis examines the potential reversibility of this injury with 2 agents: a) simvastatin, an HMGCoA reductase inhibitor, in a model independent of any reduction in lipids and 2) high dose aspirin. Hypercholesterolaemia led to a decrease in NO bioavailability, in association with a decrease in the enzyme, endothelial nitric oxide synthase and increased oxidative stress. In addition, there was an increase in the pro—inflammatory transcription factor, NF—KB, in the intima of the epicardial coronary arteries. Moreover, activated NF—KB was present in macrophages, foam cells and vascular smooth muscle cells in coronary atheromatous plaque and its expression increased in unstable coronary syndromes. These data support a role for NF—KB in the pathogenesis of early atherosclerosis and the development of unstable coronary syndromes. In addition, this thesis demonstrated for the first time that simvastatin, an HMGCoA reductase inhibitor, preserves endothelium—dependent vasorelaxation in both large and small coronary vessels in porcine experimental HC, despite no reduction in plasma lipids. This effect was associated with normalisation of eNOS protein levels. Furthermore, in vivo plasma markers of oxidative stress were attenuated by treatment with simvastatin. However, there was no attenuation in the activation of the proinflammatory transcription factor, NF—KB. These studies suggest a role for the HMGCoA reductase inhibitors in reducing cardiac morbidity and mortality, beyond their effect on cholesterol levels. The current studies also demonstrated that high dose aspirin therapy preserved endothelial function in large coronary vessels. This alteration in the generation of prostanoids in favour of vasodilatation may be an important component of the therapeutic benefit of aspirin in HC-induced atherosclerosis. In summary, results of studies described in this thesis provide insights into the molecular mechanisms that may be responsible for early vascular injury in hypercholesterolaemia and its reversibility with the therapeutic agents, simvastatin and high dose aspirin