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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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Research Article Cardiology Immunology Article has an altmetric score of 5

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

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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 12

Schematic illustration of the findings of the study.

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Schematic illustration of the findings of the study.
Our study shows tha...
Our study shows that (A) in healing infarcts, the inhibitory Smad, Smad7, is overexpressed in activated myofibroblasts through a Smad3-dependent pathway. (B) Smad7 induction restrains TGF-β–mediated Smad2/3, Erk, and Akt signaling without affecting TβR activation. (C) In addition to its inhibitory effects on TGF-β cascades, Smad7 directly interacts with the receptor tyrosine kinase ErbB2 and restrains EGFR/ErbB2 activation in a TGF-β–independent manner. (D) Inhibition of both TGF-β and ErbB1/2 cascades by Smad7 restrains synthesis of structural and matricellular matrix–associated genes and attenuates myofibroblast conversion. (E) Myofibroblast-specific Smad7-mediated effects protect the infarcted heart from adverse remodeling and reduce heart failure–related mortality. Considering the role of ErbB2 in mediating sustained actions of other ErbBs in fibrotic conditions, the Smad7-ErbB2 interaction may amplify the antifibrotic effects of Smad7. Our findings suggest that Smad7 should be viewed beyond its role as a negative regulator of the TGF-β superfamily.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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