The aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as... Show moreThe aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as adipokines, inflammation, HDL-cholesterol and postprandial triglyceride response, and cholesteryl ester transfer protein (CETP). We showed that hs-CRP and GlycA as measures of inflammation, adiponectin, and leptin are not associated with clinical and subclinical cardiovascular disease in the general population. However, all may be relevant markers of disease risk. Also, postprandial triglyceride excursions, genetically-determined CETP and HDL-cholesterol, while not related with subclinical atherosclerosis in the general population, may be interesting targets to pursue in women and men separately, and in subgroups of individuals at high-cardiovascular risk. Show less
Cardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the... Show moreCardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the interplay between genetic factors and lifestyle factors (eg sleep, nutrition, physical activity) with diseases such as cardiovascular disease and risk factors for cardiovascular disease (diabetes). For example, 12 blood biomarkers associated with insulin resistance have been identified, 5 of which are specifically much higher in subjects with diabetes. In addition, it appeared that a short sleep duration and poor sleep quality are associated with poorer lipids in the blood (eg cholesterol and LDL) and more insulin resistance. With regard to sleep, 59 new genetic variants have also been identified with regard to blood lipids (HDL, LDL, triglycerides). In addition, the results indicate that a better lifestyle can also help reduce the development of new cardiovascular diseases in people with an increased genetic risk. This is particularly interesting to prevent diseases in persons at high risk. All in all, this thesis has provided new insights into the various factors that are potentially important in the development of cardiovascular disease and diabetes. Show less
Throughout evolution, humans have lived in synchrony with the natural light-dark cycle. Our bodies were used to going to sleep a few hours after dark, and waking up just before dawn. However, in... Show moreThroughout evolution, humans have lived in synchrony with the natural light-dark cycle. Our bodies were used to going to sleep a few hours after dark, and waking up just before dawn. However, in modern society the unambiguous availability of artificial light has desynchronized our biological clock from the naturally occurring day and night, with large consequences for metabolic health. This thesis sheds light on the negative health consequences of a disturbed biological clock, and elucidates novel approaches to prevent disease associated with chronic rhythm disruption, as occurs in shift work. We have identified important mechanisms through which rhythm disruption contributes to (cardio)metabolic disease, namely by exacerbating vascular inflammation and by deregulating rhythm in glucocorticoid hormone, thereby affecting the metabolic activity of tissues such as brown fat and bone. We continued by investigating two main approaches to prevent diseases associated with circadian disturbances: (1) by limiting disruption of the circadian timing system, and (2) by directly targeting the affected tissues. We found that timed feeding (1) and stimulation of the metabolic activity of brown fat (2) are both promising strategies to prevent and/or reduce (cardio)metabolic disease risk in the ever-increasing population of individuals who suffer from circadian disturbances. Show less
14q32 microRNAs are known to play a role in various forms of vascular remodelling. This thesis elucidated that snoRNAs of the 14q32 locus are also involved in vascular remodelling processes. The... Show more14q32 microRNAs are known to play a role in various forms of vascular remodelling. This thesis elucidated that snoRNAs of the 14q32 locus are also involved in vascular remodelling processes. The expression of both noncoding RNA types in the human vasculature has been found to be vascular location and vessel type specific and are therefore promising targets for future implementation in clinical practice.The second part of this thesis focuses on three different types of 14q32 microRNA expression regulation in order to affect various vascular remodelling processes. 14q32 DNA methylation, myostatin and CIRBP were tested for their effect on 14q32 microRNA expression and the (subsequent) effect on vein graft disease and tissue ischemia, restenosis and angiogenesis, respectively. DNA methylation is not correlated with 14q32 microRNA expression, but directly interacts with vascular remodelling process status. Myostatin negatively affects 14q32 microRNA expression in vascular smooth muscle cells, but not in inflammatory cells involved in restenosis. Due to this latter finding, overall restenosis was not inhibited by myostatin. Inhibition of CIRBP inhibited 14q32 microRNA expression post-transcriptionally and therefore increased in vitro angiogenesis. These promising findings provide novel indirect regulators of vascular remodelling processes and future research will elucidate the potential for clinical application. Show less
