Division of BioTherapeutics
The research of the Van Eck Group focusses on 3 interconnected research lines: 1) Identification and therapeutic targeting of key pathways/regulators in macrophages essential for prevention of atherosclerotic lesion development or stimulation of regression of existing lesions, 2) Atherosclerosis as a co-morbidity of endocrine/metabolic disorders, and 3) Atherothrombosis and the importance of megakaryocyte and platelet function.
Regression of atherosclerosis by therapeutic targeting of macrophages
A major challenge for the treatment of cardiovascular disease is to develop novel therapeutic strategies that eliminate the huge lesion burden already present in the adult population by stimulating regression of atherosclerosis.
The infiltration of monocytes into the arterial wall, their maturation to macrophages, and the subsequent accumulation of cholesterol in these macrophages via uptake of oxidatively modified low-density lipoproteins (oxLDL) is one of the hallmarks of atherogenesis. Macrophage foam cell formation is the result of a disturbed balance between the uptake of cholesterol from lipoproteins and cholesterol efflux. ABCA1 and ABCG1 are two cholesterol transporters that may act sequentially to remove cellular cholesterol. The combined deletion of macrophage ABCA1 and ABCG1 leads to massive lipid accumulation in tissue macrophages, while induction of these transporters enhances cholesterol efflux and slows down atherosclerotic lesion development. ABCA1 and ABCG1 facilitate the transfer of cholesterol to high-density lipoproteins (HDL), which subsequently deliver their content to the liver via scavenger receptor BI. Enhancement of this process named reverse cholesterol transport is a promising strategy to reduce disease burden. Using a regression model we have shown that the cholesterol efflux pump ABCA1 impedes progression of established atherosclerotic lesions after dietary cholesterol lowering. However, overexpression of ABCA1 did not result in any additional beneficial effects. Moreover, treatment with the HDL lowering agent probucol abrogated macrophage egress under regressing conditions.
Novel therapeutic strategies directly targeting macrophages in atherosclerotic lesions is of primary interest. Approaches are being developed to target small molecule nuclear receptor agonists (LXR) to macrophages in the atherosclerotic plaque to simultaneously dampen the macrophage inflammatory response and stimulate cellular cholesterol efflux.
Atherosclerosis as co-morbidity of endocrine/metabolic disorders
Hypercholesterolemia is an important risk factor for the development of atherosclerosis, amongst others by stimulating macrophage cholesterol accumulation. Cholesterol metabolism also affects cardiovascular disease by its role in an adequate stress response and the production of the anti-inflammatory hormone cortisol in the adrenals. Disruption of the function of the HDL receptor scavenger receptor BI (SR-BI/SCARBI) impairs the selective uptake of cholesterol esters from high-density lipoprotein (HDL) by the liver and adrenals. We elucidated the importance of HDL as cholesterol donor for the synthesis of adrenal-derived glucocorticoids in mice and humans (collaboration with Jan-Albert Kuivenhoven, Groningen University Medical Center). Currently, our group is also developing an increasing interest in the link between diabetes, the common endocrine/metabolic disorder and the development of atherosclerosis (collaboration with Patrick Rensen, Leiden University Medical Center).
Atherothrombosis, platelets and megakarypcytes
Acute coronary events are not the result of progressive growth of the lesion, but rather of lesion disruption and superimposed thrombus formation. Models for studying the development of atherothrombosis are largely lacking. Recently, we developed a model in which spontaneous atherothrombosis was induced in apolipoprotein E-deficient mice by small interfering RNA-mediated silencing of protein C and hence lowering the natural anti-coagulation (collaboration with Bart J.M. van Vlijmen, Leiden University Medical Center).
Numerous epidemiological studies have established an inverse correlation between high-density lipoprotein (HDL) levels and the risk for cardiovascular disease. The protective effects of HDL have primarily been attributed to its role in reverse cholesterol transport. Interestingly, also an inverse correlation between HDL levels and acute platelet-dependent thrombus formation has been found. We have shown that, accumulation of cholesterol in platelets in mouse models with impaired reverse cholesterol transport due to a genetic deletion of the HDL receptor SR-BI enhances the susceptibility to thrombosis. Platelets are formed and released into the bloodstream by megakaryocytes (Mks) that reside primarily in the bone marrow and are formed from pluripotent haematopoietic stem cells in a process called megakaryopoiesis.
Currently, we are exploring the effects of hypercholesterolemia and essential cholesterol transporters on platelet production from megakaryocytes (collaboration with Suzanne Korporaal, University Medical Center Utrecht).