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dc.contributor.advisorMacRae, Victoriaen
dc.contributor.advisorFarquharson, Colinen
dc.contributor.authorCui Lin, Linen
dc.date.accessioned2018-06-13T14:04:42Z
dc.date.available2018-06-13T14:04:42Z
dc.date.issued2018-06-30
dc.identifier.urihttp://hdl.handle.net/1842/31182
dc.description.abstractVascular calcification is a prominent cardiovascular condition found worldwide. This condition is predominantly found in the elderly population, and patients who suffer from chronic kidney disease, due to an imbalance of serum phosphate and calcium levels. For many years, vascular calcification was believed to be a passive pathological process which develops with ageing and/or lifestyle. Little has been documented about the disease until the 20th century, when interest in cardiovascular research grew amongst scientists. Indeed, vascular calcification underpins severe clinical outcomes and cardiovascular diseases have been labelled the global leading cause of death. Calcific aortic valve diseases (CAVD) is a progressive degenerative condition characterised by the development of lipo-calcification around the aortic valve leaflets leading to severe aortic stenosis and aortic regurgitation, which may ultimately lead to heart failure. At present there are no pharmaceutical therapies that can stop its progression and its molecular mechanisms are not fully understood. Recent findings have suggested that vascular smooth muscle cell (VSMC) calcification shares many common features with physiological skeletogenesis via the release of matrix vesicles (MVs), which are specialised structures that initiate mineralisation during bone formation. The ability for MVs to nucleate calcium and phosphate highly depend on their protein composition, as this may vary depending on active cell signalling and the microenvironment. This mechanism involving MV-regulated calcification has yet to be examined in CAVD. In this study, examined whether calcium and/or phosphate regulate VIC-derived MVs to induce calcification in the aortic valve. I used a primary rat valve interstitial cell (VIC) model, coupled with stenotic human valve tissues to characterise and study the mechanisms underpinning CAVD. X-ray fluorescence and diffraction analysis showed the mineral found in calcified human aortic valves to be hydroxyapatite (HA), the main component in bone. Additional imaging studies employing transmission electron microscopy (TEM) revealed particles that were similar in size and morphology to skeletal MVs. To further characterise VIC-derived MVs in vitro, I harvested MVs from rat VICs, and subsequently studied their protein composition using Isobaric tag for relative and absolute quantitation (iTRAQ) mass spectrometry. The data obtained from the proteomics analysis was compared to previous published studies on MV proteins derived from osteoblasts and VSMCs. The results showed the upregulation of numerous calcification regulators in MVs isolated from all 3 cell types, in particular, the Annexin family, which are known calcium binding proteins. Further studies conducted with Annexin 6, an established calcium regulator in arterial calcification, revealed its colocalisation with MV-enriched areas in calcified human aortic valve tissue suggesting it may play an important role in calcium regulation during CAVD.en
dc.contributor.sponsorBiotechnology and Biological Sciences Research Council (BBSRC)en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionCui L, Rashdan NA, Zhu D, Milne E, Ajuh P, Milne G, Helfrich M, Lim K, Prasad S, Lerman D, Vesey A, Dweck M, Jenkins WS, Newby D, Farquharson C, Macrae VE (2017). End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles. Journal of Cellular Physiology doi: 10.1002/jcp.25935en
dc.relation.hasversionCui L, Zhu D, Markby G, Corcoran BM, Farquharson C, Macrae VE (2017). Isolation and characterization of primary rat valve interstitial cells: a new model to study aortic valve calcification. Journal of Visualised Experiments, 129, e56126. doi:10.3791/56126en
dc.relation.hasversionTsang H, Cui L, Farquharson C, Corcoran BM, Summers KM, Macrae VE (2017). Exploiting novel valve interstitial cell lines to study calcific aortic valve disease. Molecular Medicine Reports, 17, pp 2100-2106. https://doi.org/10.3892/mmr.2017.8163en
dc.relation.hasversionCui L, Houston DA, Farquharson C, Macrae VE (2016). Characterisation of Matrix Vesicles in Skeletal and Soft Tissue Mineralisation. Bone, 87, pp 147-158. doi:10.1016/j.bone.2016.04.007en
dc.subjectcalcific aortic valve diseaseen
dc.subjectCAVDen
dc.subjectkidney diseaseen
dc.subjectmatrix vesiclesen
dc.subjectmineral crystallisationen
dc.subjectbone formationen
dc.subjectAnnexinsen
dc.subjectAnnexin 6en
dc.titleInvestigating the role of matrix vesicles during aortic valve interstitial cell calcificationen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31
dcterms.accessRightsRestricted Accessen


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