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Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis
Hadi Khalil, … , Jason Karch, Jeffery D. Molkentin
Hadi Khalil, … , Jason Karch, Jeffery D. Molkentin
Published September 11, 2017
Citation Information: J Clin Invest. 2017;127(10):3770-3783. https://doi.org/10.1172/JCI94753.
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Research Article Cardiology Cell biology

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

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Abstract

The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β–Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload–induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload–induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast–specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β–Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.

Authors

Hadi Khalil, Onur Kanisicak, Vikram Prasad, Robert N. Correll, Xing Fu, Tobias Schips, Ronald J. Vagnozzi, Ruijie Liu, Thanh Huynh, Se-Jin Lee, Jason Karch, Jeffery D. Molkentin

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Figure 6

Fibroblast-specific deletion of Smad2/3 reduces TGF-β–induced myocardial fibrosis.

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Fibroblast-specific deletion of Smad2/3 reduces TGF-β–induced myocardial...
(A) Schematic representation of PostnMCM mice crossed to Smad2- and/or Smad3-loxP mice in conjunction with an inducible heart-specific latency-escaping TGF-β mutant cDNA driven by a cardiomyocyte-specific DTG system. (B) Representative histological heart sections with GFP+ interstitial cells (white arrows) showing that the TGF-β DTG effectively mediated Cre-dependent induction of PostnMCM/+activity, facilitating R26EGFP recombination and expression, while deletion of Smad2/3 reduced total EGFP+ cells. Hearts were harvested 4 weeks after tamoxifen administration. n = 4 mice harvested. Scale bars: 10 μm. (C) Experimental schematic whereby data shown in D and E were from mice fed tamoxifen through 12 months of age. (D and E) Pictures of Masson’s trichrome–stained cardiac histological sections and quantitation of the area of fibrosis (blue staining) in the indicated genotypes of mice in the presence of the TGF-β mutant transgenic system (DTG) for 12 months. Data are shown as average fibrotic area ± SEM. n = 6–8 in each group. *P < 0.05 versus PostnMCM/+; #P < 0.05 versus DTG PostnMCM/+. P values were calculated by 1-way ANOVA with post hoc Tukey’s HSD. Scale bars: 150 μm.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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