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
Dit proeschrift beschrijft het ontstaan van ziekte in de kleine bloedvaatjes bij vrouwen en geeft een moleculaire uitleg van de synthese en het werkingsmechanisme van microRNAs (kleine RNA... Show moreDit proeschrift beschrijft het ontstaan van ziekte in de kleine bloedvaatjes bij vrouwen en geeft een moleculaire uitleg van de synthese en het werkingsmechanisme van microRNAs (kleine RNA moleculen die gen expressie reguleren) daarin. Specifieke aandacht wordt gegeven aan het mechanisme waarmee het vrouwelijk hormoon oestrogeen de functie van bloedvaatjes en het hart reguleert door een effect op deze miRs. Ook wordt de vraag beantwoord of expressie van miRs in plasma van vrouwen bruikbaar is als diagnostische marker voor ziekte van de kleine bloedvaatjes. Dit is onder andere aangetoond in een studie in vrouwen met boezemfibrilleren (een ritmestoornis in het hart). Ook is bestudeerd in transvrouwen (man-naar-vrouw transgenders) hoe oestrogeen toediening (voor de transitie operatie) een risico op het ontwikkelen van suiker ziekte. Specifieke microRNAs werden gevonden die hierin een doorslaggevende rol spelen. Deze microRNAs werden vervolgens in muizen geremd waardoor muizen een vorm van suikerziekte ontwikkelden. 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
This thesis describes a role for microRNAs in kidney (patho)physiology. First, it is shown that miR-155 negatively regulates RhoA signaling in TGF-induced endothelial-to-mesenchymal-transition ... Show moreThis thesis describes a role for microRNAs in kidney (patho)physiology. First, it is shown that miR-155 negatively regulates RhoA signaling in TGF-induced endothelial-to-mesenchymal-transition (EndoMT). EndoMT associates with reorganization of the cytoskeleton and production of extracellular matrix, and is potentially involved in the loss of microvascular capillaries in renal fibrosis. Second, we focused on ischemia/reperfusion-injury (IRI), a central event in conditions such as acute kidney injury and organ transplantation, where the renal peritubular capillary network is considered the primary site of injury. Consequently, capillary integrity is a key determinant for preservation of renal function. Systemic silencing of miR-126 impairs ischemia-induced angiogenesis, and affects mobilization of vasculogenic progenitor cells, potentially by modulating SDF-1 expression. Furthermore, overexpression of miR-126 in the hematopoietic compartment protects against renal IRI by promoting vascular integrity. We identified miR-132 to be involved in renal fibrosis. Lineage analysis of kidney stroma showed that pericytes are the major source of myofibroblasts Silencing miR-132 results in decreased pericyte differentiation towards myofibroblasts. Subsequently we demonstrated that miR-132 regulates diuresis by altering Aquaporin-2 localization in collecting ducts, which is responsible for water-reabsorption, by modulating vasopressin- and prostaglandin-dependent pathways. This thesis illustrates the essential role that microRNAs play in kidney health and disease. Show less
Rica, L. de la; Urquiza, J.M.; Gomez-Cabrero, D.; Islam, A.B.M.M.K.; Lopez-Bigas, N.; Tegner, J.; ... ; Ballestar, E. 2013
