Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure
Claudio Humeres, … , Simon J. Conway, Nikolaos G. Frangogiannis
Claudio Humeres, … , Simon J. Conway, Nikolaos G. Frangogiannis
Published December 14, 2021
Citation Information: J Clin Invest. 2022;132(3):e146926. https://doi.org/10.1172/JCI146926.
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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.

Authors

Claudio Humeres, Arti V. Shinde, Anis Hanna, Linda Alex, Silvia C. Hernández, Ruoshui Li, Bijun Chen, Simon J. Conway, Nikolaos G. Frangogiannis

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Figure 8

Effects of Smad7 on RTK activation.

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Effects of Smad7 on RTK activation. Because transcriptomic analysis iden...
Because transcriptomic analysis identified receptor tyrosine kinase (RTK) signaling as the top-ranked pathway exhibiting differential gene expression in the absence of Smad7, we used a phospho-RTK proteomic array to identify specific RTKs modulated by Smad7. Smad7-KO (S7KO) fibroblasts were compared with control cells in the presence or absence of TGF-β1. (A) Representative array images for each condition are shown and phospho-RTKs with significant differences are highlighted in the numbered boxes. (B–E) Quantitative analysis suggests that Smad7 loss is associated with accentuated activation of EGFR/ErbB1, ErbB2, ErbB4, and FGFR cascades in TGF-β1–stimulated fibroblasts. (F and G) Other phospho-RTKs such as PDGFRβ and EPH-4 are not affected by Smad7 loss. Intensity of signal was quantified in duplicate as mean pixel density. Statistical comparison (B–G) was performed using 1-way ANOVA followed by Tukey’s multiple comparison test (n = 3). *P < 0.05; ^P < 0.05, ^^P < 0.01, ^^^P < 0.001 vs. unstimulated condition.