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 fibrosis (FS3KO:38±2.2% vs. S3 fl/fl:17±3.0%, p<0.01) and increased cardiomyocyte apoptosis, suggesting protective effect of fibroblast Smad3 on cardiomyocytes during pressure-overload. Analysis of genes associated with matrix metabolism revealed that fibroblast-specific Smad3 loss markedly accentuated collagenase matrix metalloproteinase (MMP)8 expression. In vitro, TGF-β stimulation suppressed MMP8 synthesis by cardiac fibroblasts; the effects of TGF-β1 were Smad3-dependent. MMP8 over-expression by fibroblasts lacking Smad3 may cause matrix degradation, depriving stressed cardiomyocytes from key matrix-derived pro-survival signals.
Conclusions: In pressure overloaded myocardium, activated fibroblasts may protect cardiomyocytes from death. Fibroblast-specific Smad3 signaling mediates these protective actions, at least in part by activating a matrix-preserving fibroblast phenotype that stabilizes the matrix surrounding the pressure-overloaded cardiomyocytes, thus transducing pro-survival signals.
Author Disclosures: I. Russo: None. M. Cavalera: None. Y. Su: None. N. Li: None. S.J. Conway: None. J.M. Graff: None. N.G. Frangogiannis: None.
- © 2016 by American Heart Association, Inc.