The research described in this thesis shows that hypercholesterolemia, a well-established risk factor for atherosclerosis, can impact skin lipid pool and barrier function already at young age. In... Show moreThe research described in this thesis shows that hypercholesterolemia, a well-established risk factor for atherosclerosis, can impact skin lipid pool and barrier function already at young age. In the field of atherosclerosis, we showed that the small peptide Lyp-1 can be used as a targeting molecule in liposomal formulations to deliver liver X receptor agonist to plaque resident foam cells/lipid-rich macrophages. Elucidation of the mechanisms underlying the intercommunication between plasma lipids and skin lipids may also bring valuable opportunities to prevent and treat dermatological pathologies in dyslipidemic patients; perhaps in combination with anti-atherogenic therapies. Thus, by deepening our knowledge we may improve our advice to the patients and ultimately improve their quality of life. Show less
Murine atherosclerosis models are key for investigation of atherosclerosis pathophysiology and drug development. However, they do not feature spontaneous atherothrombosis as a final stage of... Show moreMurine atherosclerosis models are key for investigation of atherosclerosis pathophysiology and drug development. However, they do not feature spontaneous atherothrombosis as a final stage of atherosclerosis. Transgenic mice expressing both the human mutant apolipoprotein E form APOE*3-Leiden and human cholesteryl ester transfer protein (CETP), i.e. APOE*3-Leiden.CETP mice, feature a moderate hyperlipoproteinemia and atherosclerosis phenotype. In contrast to apolipoprotein E deficient (Apoe(-/-)) mice, APOE*3-Leiden.CETP mice respond well to lipid-lowering and anti-atherosclerotic drugs. The aim of the study was to investigate whether silencing of anticoagulant Protein C (Proc) allows APOE*3-Leiden.CETP mice to feature thrombosis as a final stage of atherosclerosis. Female APOE*3-Leiden.CETP mice were fed a Western-type diet to induce advanced atherosclerosis, followed by an injection with a small interfering RNA targeting Proc (siProc). Presence of atherosclerosis and atherothrombosis was determined by histologic analysis of the aortic root. Atherosclerosis severity in the aortic root area of APOE*3-Leiden.CETP mice varied from type "0" (no lesions) to type "V" lesions (advanced and complex lesions). Atherothrombosis following siProc injection was observed for 4 out of 21 APOE*3-Leiden.CETP mice (19% incidence). The atherothrombosis presented as large, organized, fibrin- and leukocyte-rich thrombi on top of advanced (type "V") atherosclerotic plaques in the aortic root. This atherothrombosis was comparable in appearance and incidence as previously reported for Apoe(-/-) mice with a more severe atherosclerosis (19% incidence). APOE*3-Leiden.CETP mice with modest hyperlipidemia and atherosclerosis can develop atherothrombosis upon transient Proc-silencing. This further extends the use of these mice as a test model for lipid-lowering and anti-atherosclerotic drugs. Show less
Hoekstra, M.; Sluis, R.J. van der; Hildebrand, R.B.; Lammers, B.; Zhao, Y.; Praticò, D.; ... ; Eck, M. van 2020
C]cholesteryl oleate after intravenous VLDL-like particle injection.\nWe have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in... Show moreC]cholesteryl oleate after intravenous VLDL-like particle injection.\nWe have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.\nOBJECTIVE\nCONCLUSIONS Show less
The main underlying mechanism resulting in cardiovascular complications is the formation of atherosclerotic lesions in arteries. The progression of the lesion is hallmarked by a chronic... Show moreThe main underlying mechanism resulting in cardiovascular complications is the formation of atherosclerotic lesions in arteries. The progression of the lesion is hallmarked by a chronic inflammatory immune response in the arterial wall. Activated T helper cells differentiate into subsets, each producing a specific set of cytokines. T helper cell subsets contribute to the formation of the lesions, with a pro-atherogenic role for T helper 1 and a protective role for regulatory T cells. Cytokines of the IL-12 family play a crucial role in de differentiation of T helper cells. In this thesis I studied the role of IL-12 family members IL-27, IL-30 and IL-35 in atherosclerotic lesion formation. Furthermore the contribution of IL-37, part of the IL-1 family, was studied. In addition to modifications in lesion size and composition, I focus on the effects of the cytokines on T cell activation and differentiation. Show less
Meurs, I.; Lammers, B.; Zhao, Y.; Out, R.; Hildebrand, R.B.; Hoekstra, M.; ... ; Eck, M. van 2012
Atherosclerosis is a multifactorial disease of the large arteries and the leading cause of morbidity and mortality in industrialized countries. There is ample evidence that hypercholesterolemia (i... Show moreAtherosclerosis is a multifactorial disease of the large arteries and the leading cause of morbidity and mortality in industrialized countries. There is ample evidence that hypercholesterolemia (i.e. elevated plasma levels apo-B-containing lipoproteins) is a major causative factor in atherogenesis. It is equally clear that atherogenesis has an inflammatory component which is thought to drive the progression of the disease. However, while the lipid component in atherosclerosis development is relatively well-understood, the origin and exact contribution of the inflammatory component remains largely unknown. The aim of this thesis is to further define and delineate the contribution of the inflammatory component to the atherosclerotic process and to elucidate the link between cholesterol and inflammation in atherosclerotic lesion formation and progression. The studies of this thesis show that, besides plasma cholesterol, inflammation contributes to a substantial extent to atherogenesis. Intervention strategies directed at lowering apoB-containing lipoproteins and reducing inflammation may therefore be more effective than current lipid-lowering strategies. Direct experimental evidence for this assumption mainly comes from animal experiments as described in this thesis. Human intervention studies are necessary to evaluate whether these findings can also be translated to the human situation. Show less
In this thesis we focus on atherosclerosis as the main cause of cardiovascular disease. Since inflammation and cell death are important processes in the onset and progression of atherosclerosis, we... Show moreIn this thesis we focus on atherosclerosis as the main cause of cardiovascular disease. Since inflammation and cell death are important processes in the onset and progression of atherosclerosis, we investigate the role of several genes involved in inflammation and cell death in the vessel wall and their effect on atherosclerosis. We use several ways to modulate gene expression. Examples from different chapters are whole body deletion of TNF (2), local gene targeting of Fas Ligand to the cap of the plaque (3), conditional gene targeting of mdm2, thereby upregulating p53 (4), and beta-galactosidase (5), and pharmacological targeting of PPARs (6). In this thesis we use various mouse models of atherosclerosis, such as the apoE deficient mouse, the "humanized" apoE3*Leiden mouse and accelerated atherosclerosis induced by collar placement. Show less
