Cardiovascular diseases are among the most frequent causes of death in the world. The main underlying pathology of cardiovascular diseases is the development of atherosclerosis in the medium and... Show moreCardiovascular diseases are among the most frequent causes of death in the world. The main underlying pathology of cardiovascular diseases is the development of atherosclerosis in the medium and large-sized arteries. The role of several immune cell subsets has been identified in atherosclerosis and it has been established that the immune system contributes to initiation and progression of cardiovascular diseases. Atherosclerosis is thus currently described as a chronic inflammatory disease and both the innate and adaptive immune cells contribute to disease initiation and progression. This suggests that targeting the ongoing inflammatory response may limit atherogenesis. This thesis discusses several therapeutic immune targets to limit atherosclerotic lesion development. The results described show the interplay between lipids and the immune system and a number of anti-inflammatory strategies to reduce atherosclerotic lesion development. The studies show a clear advantage of reducing inflammation in atherosclerotic lesion development. Future (clinical) studies identifying new targets will lead to a better-personalized therapy reducing atherosclerosis. Show less
Cardiovascular disease (CVD) due to atherosclerosis is a major cause of death. In atherosclerotic lesions, two major types of macrophages can be distinguished: 1) pro-inflammatory M1-macrophages... Show moreCardiovascular disease (CVD) due to atherosclerosis is a major cause of death. In atherosclerotic lesions, two major types of macrophages can be distinguished: 1) pro-inflammatory M1-macrophages, which promote atherosclerosis and 2) anti-inflammatory M2-macrophages, which are regarded athero-protective. Hence, skewing of macrophages from an M1 to an M2-phenotype might be a promising alternative therapeutic strategy against CVD. In this PhD dissertation, using the bone marrow transplantation (BMT) technique, we examined several genes that were hypothesized to be promising drug targets to favorably modulate macrophage phenotype and function, including the classic M2 marker gene Arginase 1 (Arg1), the key regulators of M2-macrophage activation Akt2 (AKT Serine/Threonine Kinase 2) and MKP2 (MAP Kinase Phosphatase 2), and Usf1 (upstream stimulatory factor 1). Although we were successful in skewing macrophages into an M2-phenotype, this also led to accelerated foam cell formation, which counteracted the anti-inflammatory athero-protective effects of the M2-macrophage thereby limiting its therapeutic value. Overall this work underlines that modulation of macrophage polarization in atherosclerosis is feasible. However, more research is required to identify the key beneficial regulators and their overall effects in the complex microenvironment of atherosclerotic plaque before macrophage polarization can be exploited as an alternative therapeutic strategy against CVD. Show less
Cardiovascular syndromes are the major cause of death in Western societies. The main underlying pathology is atherosclerosis, a chronic disease affecting the arteries. During atherosclerosis... Show moreCardiovascular syndromes are the major cause of death in Western societies. The main underlying pathology is atherosclerosis, a chronic disease affecting the arteries. During atherosclerosis progression, LDL, or “bad” cholesterol, accumulates in the arterial wall, resulting in the formation of a lipid-rich atherosclerotic plaque. This event activates the immune system, which increases plaque inflammation. Mast cells are components of the immune system known for their role in allergy. However, it has been established that mast cells are also important in atherosclerosis. In this PhD dissertation, we explored the interaction of mast cells with other immune cells. We examined the interrelation between mast cells and T-lymphocytes and discovered that mast cells can function as antigen presenting cells in atherosclerosis and, enhance the development of an atherosclerotic plaque via a direct interaction. Nonetheless, mast cells can also act on the Natural Killer T-cells, resulting in a protective function against atherosclerosis. Importantly, we used a relatively novel technical approach to explore the characteristics of mast cells inside human atherosclerotic plaques. We found that mast cells are highly activated and thus possibly promote disease progression. In conclusion, mast cells possess both protective and harmful effects, acting as regulators of the immune response in atherosclerosis. Show less
Mast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the... Show moreMast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the site of atherogenesis, mast cells are activated to degranulate, and thereby triggered to release an abundance of preformed inflammatory mediators, notably histamine, heparin, neutral proteases and cytokines stored in their cytoplasmic secretory granules. Depending on the stimulus, mast cell activation may also launch prolonged synthesis and secretion of single bioactive molecules, such as cytokines and derivatives of arachidonic acid. The mast cell-derived mediators may impede the functions of different types of cells present in atherosclerotic lesions, and also compromise the structural and functional integrity of the intimal extracellular matrix. In the adventitial layer of atherosclerotic coronary arteries, mast cells locate next to peptidergic sensory nerve fibers, which, by releasing neuropeptides may activate mast cells to release vasoactive compounds capable of triggering local vasoconstriction. The concerted actions of arterial mast cells have the potential to contribute to the initiation and progression of atherosclerosis, and ultimately to destabilization and rupture of an advanced atherosclerotic plaque with ensuing atherothrombotic complications Show less
Despite life-style advice and the prescription of cholesterol-lowering and anti-thrombotic drugs, cardiovascular diseases are still the leading cause of death worldwide. Therefore, there is an... Show moreDespite life-style advice and the prescription of cholesterol-lowering and anti-thrombotic drugs, cardiovascular diseases are still the leading cause of death worldwide. Therefore, there is an urgent need for new therapeutic strategies focussing on atherosclerosis, the major underlying pathology of cardiovascular diseases characterized by an accumulation of lipids in an inflamed arterial/vessel wall. CD1d-restricted lipid-sensing natural killer T (NKT) cells, bridging the innate and adaptive immunity, and CD1d-expressing antigen-presenting cells are detected in atherosclerotic lesions of mice and humans. In this review we will summarize studies that point to a critical role for NKT cells in the pathogenesis of atherosclerosis and other cardiovascular diseases by the secretion of pro-atherogenic cytokines and cytotoxins. These pro-atherogenic NKT cells are potential targets for new therapeutic strategies in the prevention and treatment of cardiovascular diseases. Additionally, proteins transferring lipids during atherosclerosis, which are also important in the loading of lipids onto CD1d and possible endogenous ligands responsible for the activation of NKT cells during atherosclerosis will be discussed. Show less
The worldwide prevalence of obesity is steadily increasing. Obesity leads to insulin resistance and atherosclerosis, which are the pathologies underlying type 2 diabetes and cardiovascular disease,... Show moreThe worldwide prevalence of obesity is steadily increasing. Obesity leads to insulin resistance and atherosclerosis, which are the pathologies underlying type 2 diabetes and cardiovascular disease, respectively. Inflammation is an important factor connecting obesity to these disorders, but the exact mechanisms connecting obesity, the immune system, type 2 diabetes and cardiovascular disease are still under investigation. The research described in this thesis was performed 1) to gain more insight into the role of the immune system in obesity, dyslipidemia, insulin resistance and atherosclerosis, 2) to study whether inflammation contributes to the disadvantageous metabolic phenotype of a human population with a particularly high risk to develop type 2 diabetes and cardiovascular disease, and 3) to study the therapeutic potential of decreasing inflammation by pharmacological strategies to reduce obesity and improve glucose and lipid metabolism in pre-clinical models. The studies described in this thesis have increased our understanding of the role of inflammation in adipose tissue function and lipid metabolism during the development of type 2 diabetes and cardiovascular disease. Moreover, novel potential therapeutic strategies were identified to combat obesity, metabolic inflammation and associated metabolic disorders, such as treatment with interferons, salsalate and GPR120 agonists. Show less
Carotid atherosclerosis, a disease in which plaque builds up inside the vessel wall, is a major cause of ischemic stroke. Traditionally, atherosclerosis risk stratification is heavily based on... Show moreCarotid atherosclerosis, a disease in which plaque builds up inside the vessel wall, is a major cause of ischemic stroke. Traditionally, atherosclerosis risk stratification is heavily based on the percentage of stenosis. However, a growing body of evidence suggests that luminal stenosis may not be the only cause of symptoms but the plaque composition may be more likely to impact the disease outcome. High-resolution vessel wall magnetic resonance imaging (VWMRI) is one of the most promising modalities for visualizing and evaluating carotid atherosclerotic plaque. The quantitative assessment of carotid atherosclerotic disease requires vessel wall segmentation and plaque classification, which is generally performed by manual delineations. However, manual contour tracing is labor-intensive, time-consuming and subject to inter-observer and inter-scan variability, which makes manual image analysis impractical for studies where large volume of data needs to be processed. Therefore, the main goal of this thesis is to: 1) develop approaches to automatically, robustly and reproducibly segment the carotid vessel wall and classify the atherosclerotic plaque from multi-spectral VWMRI; 2) validate the developed methods with reference standard; 3) extract the imaging biomarkers that can assist carotid artery disease evaluation. Show less
Uusitalo, V.; Kamperidis, V.; Graaf, M.A. de; Maaniitty, T.; Stenstrom, I.; Broersen, A.; ... ; Knuuti, J. 2017
This thesis describes the role of 14q32 microRNAs in vascular remodelling. The 14q32 microRNA cluster contains 54 microRNAs in humans and is highly conserved in mammals. In part I of this thesis,... Show moreThis thesis describes the role of 14q32 microRNAs in vascular remodelling. The 14q32 microRNA cluster contains 54 microRNAs in humans and is highly conserved in mammals. In part I of this thesis, we describe the role of 14q32 microRNAs in several processes of vascular remodelling. We have shown that inhibition of several 14q32 microRNAs, miR-329, miR-494 and miR-495, results in increased neovascularisation after hindlimb ischemia in mice. In addition, inhibition of the same microRNAs reduced atherosclerotic plaque formation and restenosis in experimental mouse models under hypercholesterolemic conditions. In part II of this thesis, we zoom in to the post-transcriptional regulation of 14q32 microRNAs through RNA binding proteins. The third and last part of this thesis studies the expression of microRNAs in subcutaneous adipose tissue of critical limb ischemia patients and discusses the potential use of microRNAs as biomarker to predict the risk of amputation in these patients. In conclusion, this thesis provides novel insights in the role of 14q32 microRNAs in processes of vascular remodelling. Experimental studies have identified 14q32 microRNAs as potential therapeutic targets for treatment and prevention of atherosclerosis, restenosis and peripheral arterial disease. Show less
Bot, I.; Ortiz Zacarias, N.V.; Witte, W.E. de; Vries, H. de; Santbrink, P.J. van; Velden, D. van der; ... ; Heitman, L.H. 2017
