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 4

Myofibroblast-specific Smad7 loss accentuates postinfarction fibrosis in the border zone and in the papillary muscles.

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Myofibroblast-specific Smad7 loss accentuates postinfarction fibrosis in...
Collagen staining was performed using picrosirius red, and the collagen-stained area was assessed in the papillary muscle (PAP), infarcted (INF), border (B), and remote remodeling areas of Smad7fl/fl (S7 fl/fl) and MFS7KO hearts at 7 (A–F) and 28 days (I–N) of coronary occlusion. (G and H) Quantitative analysis demonstrates increased collagen deposition in the infarct zone of MFS7KO hearts compared with Smad7fl/fl at 7 days after infarction. (O and P) Twenty-eight days after infarction, increased collagen deposition is noted in the infarct border zone (L) and in the papillary muscle (M) of MFS7KO hearts compared with Smad7fl/fl, with comparable collagen levels in the infarct zone and the remote myocardium. For comparisons between multiple groups (G and O), 1-way ANOVA was performed followed by Tukey’s multiple comparison test. For comparisons between 2 groups (H and P), unpaired 2-tailed Student’s t test with Welch’s correction for unequal variances was performed (7 days Smad7fl/fl, n = 6; MFS7KO, n = 7; 28 days Smad7fl/fl, n = 18; MFS7KO, n = 21). *P < 0.05; ****P < 0.0001. Scale bars: 100 μm.