The aim of this thesis is to evaluate the effect of doxycycline on the proteolytic and inflammatory processes in abdominal aneurysms. This data is essential for the development of pharmaceutical... Show moreThe aim of this thesis is to evaluate the effect of doxycycline on the proteolytic and inflammatory processes in abdominal aneurysms. This data is essential for the development of pharmaceutical strategies for the stabilization of an AAA. Such an approach could reduce the need for elective surgery and endovascular repair. It has repeatedly been shown that AAA progression and rupture is related to the failure of collagen in the aortic wall. Yet the exact mechanism underlying this failure remains unknown. Furthermore, the precise mechanism of activation of collagenases and their inflammatory mediators that are responsible for the collagen turnover of AAA are unknown. In this thesis we attempt to determine how collagen metabolism is balanced in aneurysmal diseases and contribute to the knowledge which collagenases and inflammatory mediators are involved in the destruction of the collagen network in AAA disease. Moreover, we evaluate some of the effects of doxycycline on the proteases and inflammatory mediators in AAA. Analyses showed that doxycycline inhibits specific MMPs and inflammatory pathways that are involved in the collagen balance and aneurysm growth. Together, these observations provide a rationale for a randomized clinical trial studying the effect of doxycycline on aneurysm growth. Show less
The aim of the thesis was to develop metabolic analytical platforms for static and dynamic measurements that could answer biological questions for in vitro and in vivo animal models in the area of... Show moreThe aim of the thesis was to develop metabolic analytical platforms for static and dynamic measurements that could answer biological questions for in vitro and in vivo animal models in the area of lipid research. Gene profiling together with the transcriptome and metabolome data was used in combination with the LC/MS analytical platform. In terms of the analytical platforms developed, the focus was on high resolution LC/MS but not limited, as amalgamation with other platforms such as gradient gel electrophoresis (GGE) and fast protein liquid chromatography (FPLC) were explored in more detail to investigate the lipid composition of lipoprotein particles. These analytical strategies were applied to different lipid modulating biological targets as a mean to obtaining a more detailed and characteristic phenotype description directing decisions in drug search during the drug discovery process on the basis of the analytical results obtained. Additionally, the utilization of metabolic tracers was investigated further to probe dynamic changes in the biological target and animal models in question Show less
Atherosclerosis is the underlying cause of most cardiovascular diseases. The evidence to support a cholesterol-atherosclerosis link has been revealed in the past three decades. There is a growing... Show moreAtherosclerosis is the underlying cause of most cardiovascular diseases. The evidence to support a cholesterol-atherosclerosis link has been revealed in the past three decades. There is a growing consensus that therapeutic lowering of plasma VLDL- and LDL-cholesterol levels and raising of HDL-cholesterol level will reduce the risk of cardiovascular incidence. This dissertation is dedicated to the regulation of lipid metabolism pathways, both in plasma and liver, and its subsequent effects on atherosclerotic lesion progression and regression. The first part of the thesis focuses on the hepatic lipid metabolism and the pharmaceutical interventions in the liver. The second part of the thesis focuses on the concept of atherosclerotic lesion regression, shedding insights in the role of LXR activation and application of mouse models in regression studies. In Chapter 8, the results obtained from all the experiments mentioned above are summarized and discussed with respect to the implications of these studies for future investigations. Show less
Non-invasive imaging plays an increasingly important role in the diagnosis and risk stratification of coronary artery disease. Several techniques such as stress echocardiography and myocardial... Show moreNon-invasive imaging plays an increasingly important role in the diagnosis and risk stratification of coronary artery disease. Several techniques such as stress echocardiography and myocardial perfusion imaging have become available to assess cardiac function and myocardial perfusion. With the arrival of multi-slice computed tomography coronary angiography (CTA), non-invasive imaging of coronary anatomy has also become possible. CTA is a relatively new imaging technique; the objective of the thesis is therefore to explore the value of CTA for diagnosis and risk stratification of CAD in patients presenting with suspected and known CAD, in order to further define its role in clinical practice. The results of this thesis show that CTA provides important diagnostic information relative to existing non-invasive imaging strategies. In addition the detailed anatomic information obtained using CTA was shown to provide important prognostic information. CTA supplies complementary information to existing non-invasive imaging techniques, and has the potential to provide a more patient tailored approach to patient management. What remains to be determined is how CTA and non-invasive functional imaging should be integrated into clinical practice. Show less
Excessive accumulation of cholesterol by macrophage-derived foam cells is one of the characteristic features of atherosclerotic lesion development. Macrophages not only play an important role in... Show moreExcessive accumulation of cholesterol by macrophage-derived foam cells is one of the characteristic features of atherosclerotic lesion development. Macrophages not only play an important role in the initiation of the early atherosclerotic lesion, during further progression of the lesions macrophages also contribute to the formation of a necrotic core, thereby affecting the stability of the atherosclerotic plaque. Especially in the initiation of atherosclerosis the balance between cholesterol influx and efflux in macrophages is of prime importance. This balance is maintained by scavenger receptors and ATP-binding cassette (ABC) transporters, which are key mediators for macrophage cholesterol homeostasis as they facilitate the influx and efflux of lipids. Macrophages are incapable of limiting the uptake of cholesterol by scavenger receptors, including scavenger receptor class A (SR-A) and CD36. Therefore, prevention of lipid accumulation in macrophages largely depends on cholesterol efflux pathways, mainly mediated by ABC transporters. Gaining more knowledge on macrophage lipid homeostasis is of prime importance for the development of new therapeutic strategies to prevent atherosclerotic lesion development or induce regression of existing lesions. The aim of the studies described in this thesis was investigation of the role of several ABC transporters and SR-BI in (macrophage) lipid metabolism and atherogenesis. Show less
