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
Cardiovascular diseases (CVD) are the leading cause of death worldwide, and disturbances in day-night rhythms have recently been implicated as a novel risk factor for CVD. We investigated the... Show moreCardiovascular diseases (CVD) are the leading cause of death worldwide, and disturbances in day-night rhythms have recently been implicated as a novel risk factor for CVD. We investigated the effects of modulating circadian rhythms on energy metabolism using animal models and by studying plasma metaoblites and lipids in humans. Using animal studies we observed that brown adipose tissue (BAT) is strongly regulated by the biological clock, possibly via circadian glucocorticoid rhythms, and attenuated BAT activity through prolonged light exposure increases adiposity. Research focusing on the rhythm in human BAT, and regulation thereof, is necessary to confirm the translational value of our findings. We also observed that mistimed light exposure enhances atherosclerosis development, which may provide a mechanistic link between the known association between shift work and CVD. We anticipate that living according to the natural circadian rhythms presumably contributes to cardiometabolic health. Since disturbances in day-night rhythms are inevitable in modern society, in the future we may advise individuals at risk for development of CVD refrain from shift work and short sleep duration. In addition, data in this thesis may be useful to design strategies to avoid the disadvantageous metabolic effects of shift work. Show less
Bonten, T.N.; Mutsert, R. de; Rosendaal, F.R.; Jukema, J.W.; Bom, J.G. van der; Jongh, R.T. de; Heijer, M. den 2017
