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Title: Role of sphingolipids in vascular smooth muscle cell function
Author: Mathieson, Fiona A.
ISNI:       0000 0001 3621 2249
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2006
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The membrane-derived sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) have been implicated in the development of cardiovascular disease (CVD). S1P and SPC are known to accumulate in blood platelets, and are released during platelet activation. In this study, S1P and SPC were found to have differential effects on intracellular signalling pathways in vascular smooth muscle and this may have functional consequences for the development of CVD. Immunoblotting studies revealed S1P to activate the mitogenic kinase ERK 1/2, whilst SPC activated the inflammatory kinase p38MAPK. Furthermore, this differential kinase activation was found to have important consequences for transcription factor activation downstream. Using transcription factor DNA binding arrays we selected transcription factors which showed changes following S1P and SPC stimulation for further investigation. The NF-kappaB and C/EBP transcription factors are important modulators of inflammation, and were interestingly only activated following SPC stimulation in the DNA array. This was confirmed by immunoblotting and electrophoretic mobility shift assay (EMSA) to occur via a p38MAPK dependent pathway. Moreover, this was found to have functional consequences as only SPC could induce expression and production of the cytokine TNF-alpha. Therefore, SPC may play a role in the inflammatory pathway in VSM. The mitogenic transcription factor CREB, however, was activated by both S1P and SPC. This activation was dependent upon both MAPK activation and a rise in intracellular calcium. Consequently, both S1P and SPC were found to induce cellular proliferation in VSM cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available