HDL function and atherosclerosis

Atherosclerosis is a chronic pathophysiological process underlying the development of cardiovascular disease (CVD), which constitutes one of the principal causes of mortality in Austria. The majority of studies investigating the development of atherosclerosis have been focused on lipid and lipoprotein metabolism as well as on the role of inflammation. The respective contribution as well as the relationship of these mechanisms amongst each other are still a matter of speculation. Important questions could be answered in studies employing corresponding transgenic and knock-out mouse models. However, several studies yielded conflicting data pointing towards limitations of rodent models to study the development of atherosclerosis. Accordingly, wildtype mice are not prone to atherosclerosis, mass and activity of CETP a major player in lipoprotein metabolism - are absent in mouse plasma and there are distinct differences in plaque structure and composition between mice and humans. The proposed work is based on a newly developed animal model, i.e. the ApoE knockout New Zealand White rabbit. In preliminary experiments we could show that the lipoprotein pattern of these ApoE knockout rabbits was indeed more similar to that of humans when compared to the wildtype. Additionally, we found a decreased capacity of serum from ApoE knockout rabbits to promote cholesterol efflux from cholesterol laden macrophages pointing toward decreased HDL function in this animal model. These features are very likely to increase the susceptibility of these rabbits to develop atherosclerotic lesions avoiding the need for drastically increased cholesterol levels which have been shown to be associated with hepatotoxicity in wildtype NZW rabbits. Characterization of the ApoE knockout rabbit model will enable us to re-evaluate results from corresponding experiments in ApoE knockout mice and to perform a whole set of experiments to investigate mechanisms influencing the development of atherosclerosis in an animal model with high impact on the situation in humans. Accordingly, we will characterize this animal model by detailed lipoprotein analyses, as well as by measurement of expression levels and enzyme activities of proteins involved in lipoprotein metabolism including CETP, PLTP, lipoprotein lipase, LDL receptor, SR-BI and ABCA1. Next, we will examine the influence of cholesterol enriched as well as Western type diets on lipid metabolism and the development of atherosclerotic lesions in our rabbit model. Finally, we will investigate different aspects of HDL function in ApoE knockout rabbits including the role in reverse cholesterol transport, influence on endothelial function, as well as antiinflammatory and antioxidant properties. Data on HDL function in this new animal model with high impact on the situation on humans can be considered as the basis for the development of novel strategies for prevention and treatment of cardiovascular diseases in humans.

Atherosclerosis is a chronic pathophysiological process underlying the development of coronary artery disease (CAD), which constitutes one of the principal causes of mortality in Austria. Current lipid lowering therapies target the reduction of the of atherogenic low density lipoproteins (LDL) cholesterol concentration, reduction of accompanying side effects, and improvement of the atheroprotective nature of high-density lipoproteins (HDL). HDL particles are unique among lipoproteins sine they have a central role in the mechanism of reverse cholesterol transport. HDL have the ability to remove excess cholesterol from peripheral tissues and subsequently transport it toward the liver for excretion. In recent years, natural occurring bioactive compounds have been suggested as supporting therapies to conventional cardiovascular disease risk treatment. Because of its reported lipid lowering effects we investigated the effect of Matcha green tea on the HDL metabolism in an animal model closest to the situation in human. We found that Matcha green tea treatment modulated HDL function related to of reverse cholesterol transport and thereby affected the formation and progression of coronary atherosclerosis.