Smad3-Mediated Induction of Smad7 in Activated Myofibroblasts Protects the Remodeling Myocardium

TGFβs are induced in the infarcted and pressure-overloaded myocardium and play an essential role in repair and remodeling by activating Smad-dependent and Smad-independent cascades. Fibroblasts are major targets of TGFβs. Activation of Smad3 signaling in cardiac fibroblasts is crucial in post-infarction repair, mediating formation of aligned myofibroblast arrays. TGFβ responses are tightly regulated through induction of endogenous suppressive signals, such as the inhibitory Smads, that prevent excessive TGFβ signaling. We hypothesized that the inhibitory Smad7 may be induced in activated myofibroblasts infiltrating infarcted and pressure-overloaded hearts, protecting the myocardium from adverse remodeling and fibrosis by restraining TGFβ actions. Smad7 is markedly induced in infarcted and pressure-overloaded mouse hearts, and is localized in cardiomyocytes, myofibroblasts and activated macrophages. Induction of Smad7 in myofibroblasts is mediated through TGFβ/Smad3 signaling in vitro and in vivo. Mice lacking Smad7 in activated myofibroblasts (MFS7KO) and Smad7 fl/fl controls underwent non-reperfused myocardial infarction and transverse aortic constriction protocols. Following infarction, MFS7KO mice had higher mortality, worse systolic dysfunction and accentuated diastolic dysfunction when compared to Smad7 fl/fl. Following pressure overload, MFS7KO mice had accentuated interstitial and perivascular fibrosis and increased cardiomyocyte hypertrophy. In vitro, Smad7 overexpression attenuated myofibroblast conversion and reduced expression of profibrotic genes. Conversely, Smad7 knockdown promoted a matrix-synthetic fibroblast phenotype. Smad7 overexpression abrogated TGF-β-stimulated Smad2/3 and Erk activation without affecting TβRI and TβRII phosphorylation. Akt and p38 activation were unaffected by Smad7 overexpression. In conclusion, in remodeling hearts, Smad7 induction in activated myofibroblasts restrains fibrosis, negatively regulating Smad2/3 and Erk signaling through actions downstream of the TβRs. The protective effects of fibroblast Smad7 in cardiac remodeling may have important therapeutic implications for heart failure patients.