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dc.contributor.authorRoss, Andrewen
dc.date2009-07-02 19:02:52.281
dc.date.accessioned2009-07-03T19:20:33Z
dc.date.available2009-07-03T19:20:33Z
dc.date.issued2009-07-03T19:20:33Z
dc.identifier.urihttp://hdl.handle.net/1974/1980
dc.descriptionThesis (Master, Pharmacology & Toxicology) -- Queen's University, 2009-07-02 19:02:52.281en
dc.description.abstractManipulations to cyclic nucleotide populations show considerable promise in the treatment of vasculopathies associated with luminal narrowing and PDE inhibition currently represents one of the most selective methods of clinically modifying levels of these second messengers. Many cardiovascular diseases are associated with a change in vascular smooth muscle cell (VSMC) phenotype, resulting in a hyperproliferative cell devoid of contractile properties. This cell has been defined as “synthetic/activated” and differs from the normal “contractile/quiescent” VSMC in several aspects. Previous investigations have established that phosphodiesterase 1C (PDE1C), a PDE not produced in contractile/quiescent VSMCs is upregulated, and the functionally dominant PDE in the presence of calcium in these cells. This study looked to establish a role for PDE1C in synthetic/activated VSMCs as it relates to the management of VSMC phenotype. Herein, we show that RNAi mediated knockdown of PDE1C decreased expression of phenotype-dependent markers in HASMCs including PDGF-alpha receptor, l-caldesmon, and TRPC1, while the expression of other markers, including PKG, vinculin, and beta-1 integrin were unaffected. Treatment with PDE1C siRNA also reduced cell migration, proliferation, and the ability of HASMCs to bind extracellular matrix proteins. These effects were mediated without any major changes in global cAMP levels. Furthermore, a novel interaction between PDE1C and the TRPC cation channel was identified that may establish a role for PDE1C in calcium-cAMP mediation. These findings establish an important role for PDE1C in the synthetic/activated HASMC, both phenotypically, and at the sub-cellular level.en
dc.format.extent1893148 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectPDE1Cen
dc.subjectVSMCen
dc.titleThe Role of Ca²⁺/CaM-Stimulated Phosphodiesterase 1C in Vascular Smooth Muscle cells of the Synthetic/Activated Phenotypeen
dc.typethesisen
dc.description.degreeM.Sc.en
dc.contributor.supervisorMaurice, Donald H.en
dc.contributor.departmentPharmacology and Toxicologyen
dc.degree.grantorQueen's University at Kingstonen


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