The studies described in this thesis have contributed to the discovery of CETP as a biomarker for the hepatic macrophage content, a hallmark of NASH for which no non-invasive diagnostic method is... Show moreThe studies described in this thesis have contributed to the discovery of CETP as a biomarker for the hepatic macrophage content, a hallmark of NASH for which no non-invasive diagnostic method is currently available, and discovery of novel therapeutic modalities for atherosclerosis and NASH. First of all, we gained more insight into the true cellular origin of CETP (i.e. the liver macrophage), and the mechanisms underlying the CETP-lowering effects of HDL-raising agents (i.e. by reducing the hepatic macrophage content). We extrapolated the association between the reduction of hepatic lipid content and plasma CETP concentration upon lipid-lowering interventions from mice to humans. Furthermore, we demonstrated the role of CETP in discrepant effects of rHDL on VLDL metabolism between mice and humans, and reported a species difference in the central regulation of hepatic VLDL metabolism by NPY between mice and rats, which underscores a general concern in animal research in view of extrapolating findings from specific animal studies to explain observations done in humans. Additionally, we demonstrated that CORT has long-lasting beneficial effects on atherosclerosis development suggesting a possibility for therapeutic application of anti-inflammatory agents in CVD. Finally, we described GLP-1 receptor agonism as a novel strategy to improve lipid metabolism and hepatic inflammation, which may result in novel strategies to treat both atherosclerosis and NASH. Show less
In this thesis we reported our investigations of the relationship between soil-transmitted helminths (STH) and a number of outcomes, in particular malaria, insulin resistance (a marker for type-2... Show moreIn this thesis we reported our investigations of the relationship between soil-transmitted helminths (STH) and a number of outcomes, in particular malaria, insulin resistance (a marker for type-2 diabetes (T2D)) and atherosclerosis (a marker for cardiovascular diseases (CVD)) on Flores island, Indonesia. In the study on Flores Island, the use of albendazole as a single dose at three monthly intervals decreased helminth infections significantly. However, this intensive deworming could not eliminate helminth infections. Despite no effect on malaria parasitemia and clinical symptoms was found, we noted that in vitro immune responses were improved after albendazole treatment and significant increases in malaria-specific and mitogen-induced tumor necrosis factor and interferon _ cytokine production were observed. We also reported that helminth infections are associated with improved insulin sensitivity and lower risk factors for CVD. A possible approach to confirm our results will be a long-term, well-powered, placebo controlled (adequate) anthelminthic trials to investigate asymptomatic malaria (in area where clinical malaria is highly prevalent); as well as to study whether alleviation of helminthic pressure is inversely correlated with anti-inflammation, lipid levels and insulin sensitivity, and therefore leads to an accelerated development of T2D and CVD. Show less
Atherosclerose wordt veroorzaakt door een combinatie van verhoogde cholesterolniveaus en een chronische ontstekingsreactie. Deze ontstekingsreactie is het gevolg van een verstoorde balans tussen... Show moreAtherosclerose wordt veroorzaakt door een combinatie van verhoogde cholesterolniveaus en een chronische ontstekingsreactie. Deze ontstekingsreactie is het gevolg van een verstoorde balans tussen slechte, agressieve en goede, beschermende ontstekingscellen. In dit proefschrift wordt onderzocht hoe deze verstoorde balans in atherosclerose hersteld kan worden. Het onderzoek richt zich hierbij enerzijds op het remmen van de slechte ontstekingscellen en anderzijds op het stimuleren van de goede ontstekingscellen. Dit kan bereikt worden door de werking van costimulatoire en coinhibitoire eiwitten te be_nvloeden. Deze eiwitten zijn aanwezig op het celoppervlak van heel veel verschillende ontstekingscellen en bepalen of een ontstekingscel agressief of beschermend is. Costimulatoire eiwitten zorgen voor de activatie van een ontstekingscel, terwijl coinhibitoire eiwitten ontstekingscellen remmen. Blokkade van de costimulatoire eiwitten OX40L en CD30L remt atherosclerose, terwijl blokkade van het coinhibitoire eiwit Tim-3 atherosclerose verergert. Stimulatie van het coinhibitoire eiwit TIGIT vermindert de functie van T cellen. Een andere manier om de balans tussen goede en slechte ontstekingscellen te herstellen is door het aantal goede ontstekingscellen, zoals regulatoire T cellen en myeloid derived suppressor cellen, te laten toenemen. Eliminatie van regulatoire T cellen tot meer atherosclerose, terwijl een enorme expansie van regulatoire T cellen en myeloid derived suppressor cellen beschermend is. Show less
Cardiovascular diseases remain the major cause of death throughout the world and can be primarily attributed to atherosclerotic vascular disease leading to stroke and coronary heart disease (CHD).... Show moreCardiovascular diseases remain the major cause of death throughout the world and can be primarily attributed to atherosclerotic vascular disease leading to stroke and coronary heart disease (CHD). Improved primary prevention and the introduction and subsequent optimization of percutaneous coronary interventions (PCI) for myocardial ischemia due to obstructive CHD have significantly improved patient outcome and reduced morbidity and mortality. The insight into disease pathology has however expanded tremendously over the past decade and continuing research has shifted the focus of interest towards post-interventional accelerated atherosclerosis development due to a dysfunctional (auto) immune inflammatory response, responsible for vascular remodeling, re-occlusion and recurrence of symptoms. The aim of this thesis therefore was to investigate the role of the immune system in this pathophysiological process that ultimately results in post-interventional atherosclerotic vascular remodeling and apply this insight for the development of new immune-modulatory therapies in a preclinical setting. Show less
In this thesis, the role of the liver and lungs in atherosclerosis development were studied. The liver plays an important role in lipid metabolism and inflammation, the two main processes involved... Show moreIn this thesis, the role of the liver and lungs in atherosclerosis development were studied. The liver plays an important role in lipid metabolism and inflammation, the two main processes involved in atherogenesis. We show that continuous enhanced inflammation in hepatocytes increased the hepatic production of VLDL and aggravated atherosclerosis development in hyperlipidemic APOE*3-Leiden (E3L) mice as compared to control E3L mice. Poor lung function, most commonly caused by chronic obstructive pulmonary disease (COPD), is a risk factor for atherosclerosis development. To this end, we investigated whether elastase-induced alveolar wall destruction, a model for COPD, would worsen atherosclerosis development in E3L mice. No difference in atherosclerotic lesion size was observed between mice after elastase or vehicle instillation, indicating that alveolar destruction per se is not responsible for the increased risk for atherosclerosis in COPD patients. Furthermore, we studied the anti-atherosclerotic effects of resveratrol which can be found in red wine and Asian medicinal herbs. Hyperlipidemic E3L.CETP mice were fed a diet without (control) or with resveratrol, atorvastatin, or both. Resveratrol protected against atherosclerosis development, but did not add to the anti-atherogenic effects of atorvastatin. Finally, the clinical implications and future perspectives of these results are discussed. Show less
This thesis describes the use of MRI contrast agents and vessel wall parameters to image different stages of atherosclerosis. Chapter 2 summerizes different MRI contrast agents targeted towards... Show moreThis thesis describes the use of MRI contrast agents and vessel wall parameters to image different stages of atherosclerosis. Chapter 2 summerizes different MRI contrast agents targeted towards vulnerable plaques that have been presented in literature. Chapter 3 illustrates accumulation of paramagnetic micelles and liposomes in atherosclerosis, yet have complex kinetics when followed over time. In chapter 4 the use of self-gated MRI was validated to detect contrast agent accumulation in atherosclerotic plaques and assess the vessel wall compliance. The potential of both techniques to monitor plaque progression and anti-atherosclerotic therapy was assessed. In chapter 5 we developed a scavenger receptor-A1 targeted USPIO to detect vulnerable lesions. Chapter 6 describes the application of VCAM-1 targeted USPIO. Imaging at different time points, allows to discriminate early plaques from advanced lesions and can be used to monitor treatment response in ApoE-/- mice. In Chapter 7 an E-selectin targeted USPIO was validated. This USPIO allowed discrimination of lesions rich in macrophages from early lesions. In Chapter 8 we developed a micelle encapsulating rosiglitazone. Targeted delivery to the plaque lead to an anti-atheroscle rotic response without cardiac side-effects. Finally in Chapter 9 the potentials and pitfalls of histological validation of MRI contrast agents are illustrated. Show less
Gerretsen, S.; Kessels, A.G.; Nelemans, P.J.; Dijkstra, J.; Reiber, J.H.C.; Geest, R.J. van der; ... ; Leiner, T. 2013
