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Title: Actions of Advanced Glycation Endproducts (AGE) on coronary artery vascular smooth muscle cells
Author: David, Kanola Caraline Catherine
ISNI:       0000 0001 3406 7287
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2007
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Background:- Diabetes mellitus (OM) is a metabolic disorder commonly associated with advanced glycation endproducts (AGEs) and the specific receptor for AGE (RAGE). Cardiovascular disease is the main cause of mortality in patients with OM. Accordingly, accelerated atherosclerosis and AGEs are. common pathological features of OM. Chronic AGE exposure and AGE-activated intracellular signalling mechanisms were examined in coronary arteries as a causative link for the phenotypic modulation of VSMC associated with the severe atherosclerotic complications seen in diabetic patients. Methods and Results:- Cultured porcjfle coronary artery vascular smooth .muscle (CVSM) cells exposed to AGE for 96 hours were used as a relevant diabetic model. Calcium imaging studies and electrophysiology studies revealed chronic AGE treatment lead to significantly enhanced intracellular Ca2+ release and sustained activation of Ca2+-sensitive membrane ion channels, respectively, using agonists to evoke intracellular Ca2+ mobilization. Intracellular Ca2+ release from caffeinesensitive intracellular stores was enhanced in CVSM cells with AGE treatment, suggesting an upregulation of RyRs, or distinct RyR subtype expression. Brd U proliferation assay results confirmed proliferation was significantly increased in AGEtreated CVSM cells, which was abolished with cyclosporin A (CsA). Calcineurin activity, nuclear factor of activated T-cells (NFAT)-binding and RAGE expression were all significantly increased in CVSM cells after AGE exposure for 96 hC?urs. Conclusions:- This study concludes that the activation of the Ca2+-dependent calcineurin/NFAT pathway is responsible for the increased proliferative response in CVSM cells chronically exposed to AGE. An upregulation of the RAGE receptor after 96 hours AGE treatment mediates the phenotypic modulation of porcine coronary VSMC from a fully differentiated contractile phenotype to a dedifferentiated synthetic proliferative phenotype. The results of this study suggest that the uncontrollable proliferation of VSMCs associated with the accelerated atherosclerosis seen in diabetic coronary vasculature is partly due to the irreversible formation and deposition of AGEs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available