Abstract
Atherosclerosis is the primary cause of cardiovascular events such as angina pectoris and myocardial infarction, which together with stroke are responsible for around 50% of all deaths in the United States and Europe. Usually atherosclerosis develops over several decades and leads to a progressive narrowing of arterial vessels. Hypercholesterolemia is an established driving force. Therapeutic alternatives are available, but still not all patients reach their treatment goals. Therefore there is still a need for new strategies to optimize plasma cholesterol levels and reduce the development of atherosclerosis.
This study aims: to explore basic components involved in the metabolism of atherogenic lipoproteins such as the very low-density lipoprotein receptor and to explore potential new approaches to reduce atherosclerosis. From our studies the following conclusions could be drawn:
* The VLDLR is a strong candidate for mediating VLDL effects on synthesis and secretion of PAI-1 in endothelial cells.
* The VLDLR is up-regulated in 3T3-L1 cells during the differentiation into an adipocytelike phenotype, a process mediated by dexamethasone in a time and dose dependent manner, which involves a functional glucocorticoid receptor. It is not obligatory associated with the development of an adipocyte-like phenotype.
* Cholic Acid (CA) is an important player for the development of atherosclerosis since in mice, absence of CA reduces the atherosclerotic lesion area with approximately 50%. The atheroprotective effect does not seem to be mediated by FXR, but rather due to the absence of CA-dependent micelles in the intestine, reducing the cholesterol uptake.
* GC-1, a thyroid hormone receptor β-modulator, reduces atherosclerosis development in ApoE KO animals. This could be explained by a decrease in ApoB-containing lipoproteins in serum, perhaps secondary to an increased clearance via the LDLR upregulation and an increased BA synthesis in the liver.
