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dc.contributor.supervisor Dixon, Ian M.C. (Physiology) en_US
dc.contributor.author Cunnington, Ryan H.
dc.date.accessioned 2011-09-08T16:16:36Z
dc.date.available 2011-09-08T16:16:36Z
dc.date.issued 2011-01
dc.identifier.citation Antifibrotic properties of c-Ski and its regulation of cardiac myofibroblast phenotype and contractility en_US
dc.identifier.uri http://hdl.handle.net/1993/4854
dc.description.abstract Cardiovascular disease is a leading cause of death and a major economic burden in the developed and developing world. Many heart diseases, including post-myocardial infarction, include a fibrotic component with remodeling of the extracellular matrix in the myocardium. Cardiac myofibroblasts are non-myocyte cells derived from relatively quiescent fibroblasts and are the main mediators of collagen remodeling in disease states. TGF-β is recognized as an important contributor to adverse cardiac remodeling in heart disease. In this study we have investigated the role of c-Ski, which is an endogenous TGF-β inhibitor, in controlling/regulating myofibroblast function and phenotype. We have developed an adenoviral overexpression system to study these endpoints using Western blot, immunofluorescence, MTT assay, flow cytometry, procollagen type I amino terminal peptide secretion and qPCR analysis. We observed that the 95 kDa c-Ski form is overexpressed upon virus infection with adenovirus encoding c-Ski and this form of c-Ski is localized to the nucleus. c-Ski expression inhibited cardiac myofibroblast collagen synthesis and secretion as well as contractility. Phosphorylation and translocation of Smad2 into the nucleus was not affected in the presence of c-Ski overexpression. We found that c-Ski overexpression was associated with diminution of the myofibroblastic phenotype with reduced α-smooth muscle actin and extra domain-A fibronectin expression (but not non-muscle myosin heavy chain B expression). c-Ski may reduce cell viability via the induction of apoptosis. Finally, we have elucidated a putative mechanism for c-Ski-mediated reduction of myofibroblast phenotype through the upregulation of the homeodomain protein Meox2. Adenoviral overexpression of Meox2 was associated with a significant reduction of α-smooth muscle actin and extra domain-A fibronectin expression in a similar manner to that of c-Ski overexpression. Thus we have identified c-Ski as being an antifibrotic protein as well as a novel mechanism for modulation of cardiac myofibroblast phenotype, possibly through the induction of Meox2 expression. en_US
dc.publisher American Journal of Physiology Cell Physiology en_US
dc.subject myofibroblast en_US
dc.subject c-Ski en_US
dc.title Modulation of myofibroblast phenotype and function by c-Ski en_US
dc.degree.discipline Physiology en_US
dc.contributor.examiningcommittee Stephens, Newman L.(Physiology) Czubryt, Michael P.(Physiology) Wigle, Jeffrey T. (Biochemistry and Medical Genetics) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note October 2011 en_US


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