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Modulation of myofibroblast phenotype and function by c-Ski

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.

Identiferoai:union.ndltd.org:MANITOBA/oai:mspace.lib.umanitoba.ca:1993/4854
Date01 1900
CreatorsCunnington, Ryan H.
ContributorsDixon, Ian M.C. (Physiology), Stephens, Newman L.(Physiology) Czubryt, Michael P.(Physiology) Wigle, Jeffrey T. (Biochemistry and Medical Genetics)
PublisherAmerican Journal of Physiology Cell Physiology
Source SetsUniversity of Manitoba Canada
Detected LanguageEnglish

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