Atherosclerosis is the main underlying pathology of cardiovascular disease. Atherosclerosis is caused by an immune response which is directed against (modified) lipoproteins which accumulate in the... Show moreAtherosclerosis is the main underlying pathology of cardiovascular disease. Atherosclerosis is caused by an immune response which is directed against (modified) lipoproteins which accumulate in the vessel wall. Over time, this accumulation of lipids and immune cells induce morphological abnormalities in the vessel wall which cause the vessel lumen to narrow. This narrowing of the lumen (stenosis) causes ischemia in the downstream tissue. Prolonged ischemia causes myocardial ischemia and/or stroke. The research described in my thesis examines a well-recognized risk factor of atherosclerosis, being dyslipidemia, from an entirely new perspective. More specifically, it describes how dyslipidemia affects intrinsic metabolic processes in T cells, the conductors of the immune response characterizing atherosclerosis, and how this affects their function. My research has contributed to knowledge on the pathophysiology of atherosclerosis and might one day pave the way for the development of novel therapeutic approaches to treat cardiovascular disease. 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
During this research project we studied circulating cells in the blood of people with cardiovascular disease, we investigated if these cells could be used as biomarkers for future cardiovascular... Show moreDuring this research project we studied circulating cells in the blood of people with cardiovascular disease, we investigated if these cells could be used as biomarkers for future cardiovascular incidents. We specifically looked at circulating immune cells such as monocytes, T cells and neutrophils. It was shown that both specific subsets of monocytes as well as neutrophils could be used to predict cardiovascular events in patients with cardiovascular disease. Surprisingly it was shown that different cell subsets were predictive for cardiovascular events in men and women. Investigating the difference between men and women further we show that the acute immune response in during cardiovascular disease is different between men and women. While the response in males was skewed towards a monocyte response, in women the acute response was skewed towards a T cell response. The research presented in this thesis shows that our knowledge of the gender specific immune response in cardiovascular disease is limited and further research is necessary. Show less
Atherosclerosis is a chronic inflammatory disease in which lipids and cells of the immune system accumulate in the vessel wall. Clinical complications, such as a myocardial infarction or stroke may... Show moreAtherosclerosis is a chronic inflammatory disease in which lipids and cells of the immune system accumulate in the vessel wall. Clinical complications, such as a myocardial infarction or stroke may occur when advanced atherosclerotic lesions become unstable and rupture. In this thesis, the influence of the psychological stress response and stress-related neuropeptides on vascular inflammation and atherosclerotic lesion development has been investigated. We demonstrated that acute stress results in activation of a potent type of immune cell in the vessel wall, the mast cell, leading to increased inflammation and atherosclerotic plaque destabilization. Furthermore, we have shown that (peri)vascular mast cell activation leads to neutrophil recruitment, thus aggravating the local inflammatory response. In addition, we demonstrated increased expression of neuropeptide Y in advanced atherosclerotic lesions and that overexpression of this peptide results in increased lesion development. These insights emphasize a contributing role for psychological stress to atherosclerotic lesion development and as a risk factor for acute cardiovascular syndromes and opens up new avenues for possible future anti-inflammatory therapies to reduce the risk of cardiovascular disease. Show less
Atherosclerosis is the main underlying pathology of cardiovascular disease, the largest single cause of death in industrialized countries, and current treatment is still largely insufficient. In... Show moreAtherosclerosis is the main underlying pathology of cardiovascular disease, the largest single cause of death in industrialized countries, and current treatment is still largely insufficient. In recent years it has become evident that immune responses contribute to atherosclerosis. Therefore, during my PhD studies I focused on developing a therapy to induce and expand anti-inflammatory immune cells to reduce ongoing immune responses and atherosclerosis. I used the approach of cellular therapy and examined the effect of several different anti-inflammatory immune cells. For example, I made use of mesenchymal stem cells, which have previously been used to improve cardiac repair after myocardial infarction and were found to have anti-inflammatory properties. Additionally, I used drugs, e.g. inhibitors of protein degradation, and biologics, e.g. components of heat-killed bacteria, to directly increase the amount of anti-inflammatory immune cells. An interesting side-effect of some treatments was that they additionally reduced cholesterol levels. In summary, I have shown in pre-clinical models that immune cell-based therapies are promising for the treatment of atherosclerosis. As atherosclerosis is determined by both high cholesterol levels and inflammation reducing immune responses will greatly contribute to a better treatment of cardiovascular patients in the (near) future. Show less
Atherosclerosis is a chronic inflammatory disease, consisting of the buildup of lipids in the vessel wall. Advanced lesions may become unstable and rupture, leading to major cardiovascular... Show moreAtherosclerosis is a chronic inflammatory disease, consisting of the buildup of lipids in the vessel wall. Advanced lesions may become unstable and rupture, leading to major cardiovascular complications such as myocardial infarction or stroke. In this thesis, the role of the innate immune system in atherosclerosis has been investigated. We have shown that inhibition of complement component C5a results in reduced atherosclerotic lesion formation as well as reduced lesion destabilization. Also, we have provided evidence that activation of mast cells surrounding the atherosclerotic lesion results in increased accumulation of the neutrophil, thus aggravating the local inflammatory response. Moreover, we have investigated the effect of microRNA inhibition of atherosclerosis. MicroRNAs are short non-coding RNA strands with the ability to modulate the expression of multiple genes. With a unique Reversed Target Prediction we have identified microRNAs that are predicted to affect multiple atherosclerosis-related genes. We inhibited one of these predicted microRNAs: microRNA-494, and investigated its role in vivo. Interestingly, we observed a striking reduction in atherosclerotic lesion formation, as well as an increase in lesion stability. Show less
With the use of combinatorial phage display, solid phase peptide synthesis and a multidiscipline of molecular and cellular assays in vascular biology, the research described in this thesis has... Show moreWith the use of combinatorial phage display, solid phase peptide synthesis and a multidiscipline of molecular and cellular assays in vascular biology, the research described in this thesis has resulted in the identification of two novel peptides targeting to SR-AI and CD40 respectively which hold promise as targeted contrast agents for the diagnosis of atherosclerosis symptom. In addition, a peptide named VIVIT and its derivatives had been discovered and synthesized which constitute a more selective and less toxic drug candidate than currently used immunosuppressant cyclosporine A or FK506, leading to new generation immunosuppressants and therapeutics for autoimmune diseases such as rheumatoid arthritis or allograft transplantation and cardiovascular disorders including atherosclerosis, restenosis and cardiac hypertrophy. Show less
