Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure

Abstract

Repair of the infarcted heart requires TGF-β/Smad3 signaling in cardiac myofibroblasts. However, TGF-β–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 nonreperfused infarction, Smad3 activation triggered Smad7 synthesis in α-SMA + infarct myofibroblasts, but not in α-SMA – PDGFRα + 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 effects on TGF-β cascades involved deactivation of Smad2/3 and non-Smad pathways, without any effects on TGF-β 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-β–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-β–induced negative feedback mechanism that inhibits postinfarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-β–independent fibrogenic actions of ErbB2.

The role of endogenous Smad7 in regulating macrophage phenotype following myocardial infarction

“…The inhibitory Smad, Smad7, serves as a potent endogenous negative regulator of TGF‐β actions, restraining TGF‐β signaling cascades in many different cell types 31,75–77 . In macrophages, the role of Smad7 as a negative regulator of TGF‐β‐mediated actions remains controversial, as various studies have produced conflicting results.…”

“…The inhibitory Smad, Smad7, serves as a potent endogenous negative regulator of TGF-β actions, restraining TGF-β signaling cascades in many different cell types. 31,[75][76][77] In macrophages, the role of Smad7 as a negative regulator of TGF-βmediated actions remains controversial, as various studies have produced conflicting results. Experiments in a viral infection model suggested that induction of Smad7 in macrophages may trigger inflammation, abrogating the anti-inflammatory effects of TGF-β.…”

“…31 Moreover, a growing body of evidence suggests that Smad7 may also have TGF-β independent actions. 32 The role of Smad7 in immune cells is controversial, as experimental studies have produced conflicting results. It has been suggested that Smad7 mediates the anti-inflammatory effects of TGF-β, by binding to the adaptors TAB2 and TAB3, and by inhibiting TAK1 recruitment to TRAF2, 33 thus blocking pro-inflammatory TNF signaling, and attenuating NF-κB activation.…”

Cardiac Remodeling After Myocardial Infarction: Functional Contribution of microRNAs to Inflammation and Fibrosis

“…Our group was the first to demonstrate that two different miRs, namely miR-92a ( 26 ) and miR-195 ( 35 ), act as transcriptional regulators of SMAD7, an inhibitor of α-SMA, which is a well-established marker of myofibroblast activation ( 58 ). We found that miR-92a is significantly upregulated in cardiomyocyte-derived exosomes and in fibroblasts isolated after MI compared with SHAM conditions, indicating that miR-92a is transferred to fibroblasts in form of exosomal cargo and is essential for the activation of cardiac myofibroblast ( 26 ).…”

Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction

“…They revealed that Smad7 had an inhibitory effect on TGF-β expression in fibroblasts by promoting TβR and R-Smad turnover, leading to the downregulation of Smad2 and Smad3 molecules. This resulted in reduced myofibroblastic activity and decreased synthesis of EMPs [ 122 ]. Additionally, the TGF-β1/Smad signaling pathways are regulated by Slit2.…”