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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 3

Fibroblast-specific deletion of canonical TGF-β signaling reduces myocardial fibrosis in mice.

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Fibroblast-specific deletion of canonical TGF-β signaling reduces myocar...
(A and B) Masson’s trichrome–stained histological pictures and quantitation of the area of fibrosis (blue) in hearts from the indicated genotypes of mice with PostnMCM/+ after 12 weeks of TAC injury and tamoxifen treatment. Average fibrotic area ± SEM. n = 8–10 mice in each group. *P < 0.05 versus sham operated; #P < 0.05 versus PostnMCM/+ TAC at 4 or 12 weeks. P values were calculated by 1-way ANOVA with post hoc Tukey’s HSD. (C and D) Masson’s trichrome–stained histological photographs and quantification of the area of fibrosis in hearts from the indicated mice crossed with Tcf21MCM/+ after 4 weeks of TAC injury and tamoxifen treatment. Average fibrotic area ± SEM. n = 6–9 mice in each group, *P < 0.05 versus sham operated; #P < 0.05 versus Tcf21MCM/+ TAC at 4 weeks. P values were calculated by 1-way ANOVA with post hoc Tukey’s HSD. (E and F) Masson’s trichrome–stained histological photographs and quantification of the area of fibrosis in αMHCMCM/+ and cardiomyocyte-specific deletion of Smad2/3 from hearts after 12 weeks of TAC injury. Mice were injected 5 times with 100 μl of 0.5 mg/ml of tamoxifen 15 days before injury. Average fibrotic area ± SEM. n = 7–9 mice in each group. *P < 0.05 versus sham operated. P values were calculated using 1-way ANOVA with post hoc Tukey’s HSD. Scale bars: 150 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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