Cardiovascular disease (CVD) is a major cause of death worldwide. The underlying cause of most CVD is atherosclerosis. Atherosclerosis is characterized by progressive plaque build-up in the... Show moreCardiovascular disease (CVD) is a major cause of death worldwide. The underlying cause of most CVD is atherosclerosis. Atherosclerosis is characterized by progressive plaque build-up in the arterial wall.Noncoding RNAs (ncRNAs) are RNAs that are not translated into protein. This thesis focuses on two types: microRNAs and small nucleolar RNAs (snoRNAs). MicroRNAs inhibit the production of proteins and act on multiple proteins simultaneously. In CVD, many different proteins are involved. Changing expression of one microRNA can therefore have a major impact.Numerous snoRNAs have been associated with diseases, including CVD. The function of half of the human C/D box snoRNAs, however, is unknown.The first aim of this thesis is to investigate inhibition of microRNA-494-3p in advanced atherosclerosis. The second aim is to elucidate the function of SNORD113-6, a snoRNA that is involved in CVD.The thesis shows that inhibition of microRNA-494-3p halts plaque progression and increases stability of advanced plaques. This reduces the risk of e.g. a myocardial infarction.Furthermore, SNORD113-6 influences the function of fibroblasts, scar cells, and thus plays a role in maintaining function of our blood vessels.These insights may open up new therapeutic possibilities in future treatment of CVD. 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
