The aim of this thesis was to gain more insight in the involvement of inflammatory processes in vessel wall remodeling seen after PTA or bypass surgery and put these processes in the perspective of... Show moreThe aim of this thesis was to gain more insight in the involvement of inflammatory processes in vessel wall remodeling seen after PTA or bypass surgery and put these processes in the perspective of restenosis, vein graft failure and potential therapeutic preventive strategies. Therefore, we firstly focused on inflammation in general, using the anti-inflammatory agent Dexamethasone, assessing the effects of such a broad approach on restenosis and vein graft remodeling. Then, we further focused on some specific parts of the immune system, namely Interleukin 10 (IL10), chemokines and the complement cascade. Il10 was chosen because it is one of the most studied anti-inflammatory cytokines and this property makes it a potential candidate for ant-restenosis therapy. Furthermore, it was hypothesized that chemokines are involved in vascular remodeling, since they are generally known for their regulatory properties regarding influx of inflammatory cells to tissues and this is one of the first phenomena seen in vascular remodeling. The complement cascade was studied in this context since it contains pro-inflammatory activity and some end-products of the cascade, like chemokines, are potent chemotactic agents. Show less
Venous thrombosis (VT) is a multicausal disease that is caused by the interaction of both genetic and acquired risk factors. The aim of the studies described in this thesis was to identify novel... Show moreVenous thrombosis (VT) is a multicausal disease that is caused by the interaction of both genetic and acquired risk factors. The aim of the studies described in this thesis was to identify novel genes or genomic regions that contribute to the susceptibility of VT. We used two different approaches to achieve this goal: the hypothesis-based candidate gene approach and the discovery-based genome-wide approach. The candidate genes investigated are factor VII-activating protease, coagulation factor IX and four interleukin-1 related genes. As a second approach we used a genome-wide linkage approach to systematically scan the genome for genes or genomic regions that contribute to the susceptibility of venous thromboembolism (VTE). For this purpose we recruited a panel of affected sibling pairs with VTE at a young age (Genetics In Familial Thrombosis study, GIFT). Two novel susceptibility regions for VTE were identified. We screened eleven candidate genes, selected from both regions, to investigated whether variants of these genes could explain the observed linkage signals. Identification of the gene(s) and their functional variants, which are responsible for the linkage signals, will give better insights in the molecular genetics of familial thrombophilia and might be important for the diagnosis, treatment and prevention of VTE. Show less
The main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e.... Show moreThe main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e. transgenic and knock-out mouse models). Many of these genes exert their role in atherosclerosis development as a result of effects on lipoprotein metabolism and inflammation. Transgenic mouse models have also been proven to be suitable for evaluating the mechanisms underlying the anti-atherosclerotic action of experimental drugs aimed to reduce atherogenic lipoprotein levels. However, thus far no suitable animal model was present to evaluate the mechanism of action of anti-atherosclerotic effect of HDL-raising therapeutic strategies. In this thesis, we further explored the role of apolipoprotein CI (apoCI) and cholesteryl ester transfer protein (CETP) in lipoprotein metabolism, inflammation, and atherosclerosis. Furthermore, we developed a mouse model that will be suitable for testing potential high-density-lipoprotein (HDL) raising therapies as a novel strategy to treat CVD. Show less
The research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_... Show moreThe research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_-transgenic and apoc1-/- mice, we were able to identify apoCI as a potent inhibitor of triglyceride hydrolysis by inhibiting lipoprotein lipase. Since APOC1 mice have thus increased VLDL levels, and VLDL protects against bacterial infection, we studied whether apoCI could play a role in inflammation and infection. We found that apoCI was able to bind lipopolysaccharide (LPS), the main toxic component of Gram-negative bacteria. Interestingly, although other apolipoproteins which have been studied have anti-inflammatory properties, we found that apoCI is a pro-inflammatory protein. By enhancing the biological response towards LPS and Gram-negative bacteria, apoCI dose-dependently improved the anti-bacterial attack, and protected against intrapulmonal Klebsiella pneumoniae-induced sepsis. Consistent with these experimental findings we also found that subjects with high plasma apoCI levels were less prone to infection-related mortality during follow-up, independent of plasma lipid levels. Likewise, survivors of severe sepsis showed higher plasma apoCI levels as compared to non-survivors, again independent of lipid levels. Taken together, our findings indicate that apoCI is an important determinant of the inflammatory response in mice and humans. Show less
In dit promotieonderzoek is zijn de effecten van vetstapeling en ontstekingsreactie tijdens het proces van atherosclerose. We hebben aangetoond dat het ontstekingsremmende eiwit interleukine-9, een... Show moreIn dit promotieonderzoek is zijn de effecten van vetstapeling en ontstekingsreactie tijdens het proces van atherosclerose. We hebben aangetoond dat het ontstekingsremmende eiwit interleukine-9, een stof die door bepaalde immunologische cellen geproduceerd wordt, een remmende werking heeft op het ontstaan van atherosclerose in het algemeen en van vetstapeling in macrofagen in het bijzonder. Aan de andere kant blijkt uit mijn promotieonderzoek dat vetstapeling van macrofagen de gevoeligheid van deze cellen voor ontstekingen beïnvloedt. LPS is in staat om een zeer sterke ontstekingsreactie te stimuleren en om de expressie van verschillende genen die betrokken zijn bij vetstapeling te beïnvloeden. Door gebruik te maken van muizen die geen scavenger receptor BI (SR-BI) tot expressie brengen, hebben we aangetoond dat SR-BI beschermd tegen de door LPS gestimuleerde ontstekingsreactie. Tevens blijkt dat een dieet met een hoog cholesterol gehalte een grote invloed heeft op parenchymcellen in de lever. Voornamelijk FABP5 en vier nieuwe vetzuurbindende eiwitten lijken een belangrijke rol te spelen in de reactie van deze cellen op het dieet. Ook het ontstekingremmende interleukine 10, waarvan bekend is dat het atherosclerose kan remmen en een verlaging van cholesterol in het bloed kan veroorzaken, beïnvloedt vele genen betrokken bij vethuishouding in parenchymcellen van de lever. Show less
This thesis examines different risk factors, in relation to restenosis after Percutaneous coronary interventions (PCI), with its main focus on genetic markers. Restenosis is the main drawback of... Show moreThis thesis examines different risk factors, in relation to restenosis after Percutaneous coronary interventions (PCI), with its main focus on genetic markers. Restenosis is the main drawback of PCI. Genetic variance poses an opportunity to enhance stratification of individuals who will be more prone to develop restenosis. Restenosis is a multifactorial process, therefore only limited part of the number of candidate genes that are potentially involved in restenosis can be described. Since the inflammatory reaction is known to be highly important in restenosis, our study has its main focus on inflammatory markers. To examine various candidate genes and their polymorphisms we made use of the GENetic DEterminants of Restenosis (GENDER) study, a multicenter follow-up study, including 3,104 consecutive patients, who were successfully treated with PCI. In the different chapters we describe the study population and the clinical and genetic factors investigated. Furthermore, we made use of a mouse model to improve our understanding of restenosis. Our results have contributed to a better understanding of the restenotic process, they could provide novel therapeutic targets as well as contribute to development of improved risk stratification of patients who are scheduled for elective PCI, thereby creating the opportunity to individualize treatment in the future. 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
Aderverkalking (atherosclerose) is een ziekte waarbij door verdikking van de vaatwand vernauwing van slagaderen optreedt. Door deze vernauwing is het mogelijk dat er te weinig zuurstofrijk bloed de... Show moreAderverkalking (atherosclerose) is een ziekte waarbij door verdikking van de vaatwand vernauwing van slagaderen optreedt. Door deze vernauwing is het mogelijk dat er te weinig zuurstofrijk bloed de organen bereikt. In het geval van atherosclerose in slagaderen die hart of hersen van bloed moeten verzien leidt de vernauwing niet zelden tot de dood. Het feit dat atherosclerose de belangrijkste onderliggende oorzaak is van wereldwijde sterfte onderstreept het maatschappelijk belang van ontwikkeling van een adequate therapie tegen atherosclerose. In dit proefschrift werden nieuwe vaccinatietechnieken aangewend om het proces van atherosclerose tegen te gaan. Door de tolerantie voor lichaamseigen stoffen of cellen te doorbreken met deze vaccinatietechnieken bleek het mogelijk te zijn atherosclerose in muizen sterk af te remmen. Het wegnemen van de functie van ontstekingsbevorderende eiwitten (interleukinen 12 en 17) met deze vaccinatietechieken leidde tot een 70-90% afname in atherosclerose. Ook het met vaccinatie specifiek opruimen van cellen die betrokkken zijn bij atherosclerose-geassocieerde processen, zoals nieuwvaatvorming, bleek een geschikte methode te zijn om atherosclerose tegen te gaan. Het voordeel van de nieuwe vaccinatietechnieken die bij dit onderzoek zijn gebruikt is gelegen in het feit dat met enkele injecties voor lange tijd (ten minste 24 weken) bescherming tegen atherosclerose bewerkstelligd kan worden. Andere voordelen van deze vaccinaties zijn het gebrek aan afweerreacties tegen lichaamsvreemde medicijnen en de lage productiekosten van dergelijke vaccins. De combinatie van de sterke afname in atherosclerose en de bijkomende voordelen van de vaccinatietechnieken leidde in dit proefschrift tot de conclusie dat vaccinatie een belangrijke bijdrage kan leveren aan de ontwikkeling van therapieën tegen hart- en vaatziekten in mensen. Show less
The work described in this thesis was aimed at identifying the role of cell cycle and apoptosis genes in atherosclerosis. Atherosclerosis is the primary cause of cardiovascular disease, a disorder... Show moreThe work described in this thesis was aimed at identifying the role of cell cycle and apoptosis genes in atherosclerosis. Atherosclerosis is the primary cause of cardiovascular disease, a disorder occurring in the large and medium-sized arteries of the body. Although in the beginning 90s promising lipid lowering therapies predicted a strong reduction in cardiovascular deaths, in westernized societies it is still the underlying cause of about 40% of all deaths, indicating that treatment of atherosclerosis goes beyond lipid lowering solely. In addition to lipids, continuous cell growth (cell cycle) and cell death (i.e. apoptosis and necrosis) processes play a central role in the development of atherosclerosis. To investigate the role of several cell cycle and apoptosis genes (i.e. p53, Rb and Mdm2) in atherosclerosis we generated and characterized several mouse models based on site-specific recombinase (SSR) technology. The studies described in this thesis show that next to therapies aiming at lifestyle interventions, lipid therapies and regulation of inflammation, targeting cell cycle and apoptosis genes on lesional or cellular level might prove the most effective way to reduce the burden of atherosclerosis. Show less
