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

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

doi:10.1172/jci146926

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.

Highlights

The adult mammalian myocardium contains abundant fibroblasts[1],(2)
In order to examine whether Smad7 is expressed in infarct fibroblasts and myofibroblasts, we performed Smad7/ -SMA immunofluorescent staining in infarcted PDGFR GFP fibroblast reporter mice
Localization of Smad7 in myofibroblasts was confirmed by performing Smad7 staining in periostin-Cre;ROSA26EYFP mice, in which activated myofibroblasts are labeled (Supplemental Figure 1I-O)

Summary

Introduction

Following myocardial infarction (MI), fibroblasts become activated and play a critical role in repair, protecting the heart from catastrophic rupture[3],(4). The cardiac reparative response requires tight regulation of fibroblast activation. Expansion of matrix-synthetic myofibroblasts during the proliferative phase of infarct healing is followed by deactivation and acquisition of a quiescent fibroblast phenotype in the mature scar[5]. Considering the importance of timely stimulation and suppression of fibroblast activity in the healing heart, impaired myofibroblast deactivation following infarction would be expected to cause progressive fibrosis and may contribute to the pathogenesis of post-MI heart failure. Endogenous negative regulators of fibrogenic pathways may play a crucial role in protection of the infarcted heart from adverse remodeling. The molecular signals responsible for suppression of the cardiac fibrotic response following injury remain poorly understood

Methods

Results

Conclusion