Published online before print October 2, 2008

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(American Journal of Pathology. 2008;173:1275-1285.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080365

Transforming Growth Factor-β Regulates in Vitro Heart Valve Repair by Activated Valve Interstitial Cells

From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto; and the Department of Pathology, Toronto General Research Institute, University Health Network, Toronto, Canada

The regulation of valve interstitial cell (VIC) function in response to tissue injury and valve disease is not well understood. Because transforming growth factor-β (TGF-β) has been implicated in tissue repair, we tested the hypothesis that TGF-β is a regulator of VIC activation and associated cell responses that occur during early repair processes. We used a well-characterized wound model that was created by mechanical denudation of a confluent VIC monolayer to study activation and repair 24 hours after wounding. VIC activation was demonstrated by immunofluorescent localization of -smooth muscle actin (-SMA), and -SMA mRNA levels were quantified by real-time polymerase chain reaction. Proliferation and apoptosis were quantified by bromodeoxyuridine staining and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Repair was quantified by measuring VIC extension into the wound, and TGF-β expression was shown by immunofluorescent localization of intracellular TGF-β. Compared with nonwounded monolayers, VICs at the wound edge showed -SMA staining, increased -SMA mRNA content, elongation into the wound with stress fibers, proliferation, and apoptosis. VICs at the wound edge also showed increased TGF-β and pSmad2/3 staining with co-expression of -SMA. Addition of TGF-β neutralizing antibody to the wound decreased VIC activation, -SMA mRNA content, proliferation, apoptosis, wound closure rate, and stress fibers. Conversely, exogenous addition of TGF-β to the wound increased VIC activation, proliferation, wound closure rate, and stress fibers. Thus, wounding activates VICs, and TGF-β signaling modulates VIC response to injury.

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