Abstract 19315: Fibroblast Smad 3 Signaling Protects Cardiomyocytes in the Pressure-Overloaded Myocardium

Introduction: In pressure-overloaded heart, cardiac remodeling, dysfunction and fibrosis are associated with activation of TGF-β/Smad3 signaling. In vitro, Smad3 is implicated in fibroblast activation. We hypothesized that fibroblast-specific Smad3 actions may play an essential role in fibrotic remodeling of the pressure-overloaded heart. Methods and Results: In a model of pressure overload induced by transverse aortic constriction (TAC), activated fibroblasts (but not vascular cells, hematopoietic cells and cardiomyocytes) express periostin. We used periostin-Cre driver to generate mice with loss of Smad3 in activated fibroblasts (FS3KO). After 7 days of TAC, fibroblasts isolated from FS3KO hearts exhibited significantly reduced Smad3 expression, compared to Smad3 fl/fl controls. When compared with Smad3 fl/fl, FS3KO mice had a marked reduction in ejection fraction 7 days after TAC, suggesting accelerated systolic dysfunction. Depressed function in FS3KO was associated with accentuated replacement fibros...