Abstract 16793: Smad7 Induction in Activated Infarct Myofibroblasts Protects From Adverse Remodeling by Restraining TGF-beta-Mediated and Receptor Tyrosine Kinase Signaling

Cardiac repair is dependent on myofibroblast TGF-b/Smad3 signaling and subsequent formation of an organized scar. However, to prevent prolonged activation and fibrosis, TGFβ effects are tightly regulated through induction of suppressive signals, such as the inhibitory Smads, that restrain TGFβ cascades. We hypothesized that the inhibitory Smad7 may be induced in infarct myofibroblasts, protecting from adverse remodeling and fibrosis. Moreover, we dissected the molecular signals modulated by Smad7. Smad7 is markedly induced in infarct myofibroblasts through a TGFβ/Smad3 pathway. To investigate the role of endogenous Smad7 in post-infarction remodeling, we generated mice with myofibroblast-specific Smad7 loss (MFS7KO). Following non-reperfused infarction, MFS7KO mice had increased late mortality that was not due to rupture, but was associated with worse heart failure. Surviving MFS7KO mice had accentuated adverse remodeling, worse systolic/diastolic dysfunction and increased collagen deposition in the infarct border zone, in comparison to Smad7 fl/fl animals. In isolated cardiac fibroblasts, Smad7 overexpression attenuated myofibroblast conversion and profibrotic gene expression, whereas Smad7 knockdown promoted matrix synthesis. In Smad7 KO fibroblasts, overactive fibrogenic activity was associated with enhanced Smad2/3, Erk and Akt signaling, but comparable TβRI/TβRII phosphorylation, suggesting that Smad7 acts downstream of the TGFβ receptors. To dissect the mechanisms for Smad7 actions, we compared the transcriptome of Smad7 KO and WT fibroblasts, in presence/absence of TGFβ. Surprisingly, Smad7 loss had more prominent effects on receptor tyrosine kinase (RTK) cascades than on TGFβ-inducible genes. An RTK protein array identified Erbbs as targets of Smad7 in fibroblasts. Western blot showed that Smad7 restrains Erbb1 and Erbb2 signaling through effects independent of TGFβ. In conclusion, Smad7 induction in infarct myofibroblasts restrains fibrosis, by inhibiting Smad2/3, Erk and Akt signaling via actions downstream of TβRs, and through TGFβ-independent interactions with Erbb1/2. Protective effects of Smad7 in cardiac remodeling may have important therapeutic implications for heart failure patients.