GSE185767
Endogenous Smad7 restrains myofibroblast activation and protects from post-infarction heart failure by suppressing TGF-b signaling and by directly inhibiting Erbb2
Repair of the infarcted heart requires TGFß-Smad3 signaling in cardiac myofibroblasts. However, TGF-ß-driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7 may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of non-reperfused infarction, Smad3 activation triggered Smad7 synthesis in ß-SMA+ infarct myofibroblasts, but not in ß-SMA-/PDGFRa+ fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure-related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 actions on TGF-ß cascades involved de-activation of Smad2/3 and non-Smad pathways, without any effects on TGF-ß receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with Erbb2 in a TGF-independent manner and restrained Erbb1/Erbb2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-ß-induced negative feedback mechanism that inhibits post-infarction fibrosis by restraining Smad-dependent and Smad-independent TGF-ß responses, and by suppressing TGF-independent fibrogenic actions of Erbb2. Overall design: Comparison of the transcriptomic profile of In vitro cultured control and Smad7KO cardiac fibroblasts (passage 2), in presence/absence of TGF-ß stimulation. Smad7 loss was achieved via Adenoviral Cre expression in fibrobrasts isolated from Smad7 floxed animals. 4 conditions (Control, Smad7KO, Control + TGFß, S7KO + TGFß); 3 indepent samples per condition. 12 samples total.