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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3770-3783
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number10
DOIs
StatePublished - Oct 2 2017

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Fibrosis
Fibroblasts
Myofibroblasts
Pressure
Extracellular Matrix Proteins
Wounds and Injuries
Regulator Genes
Transgenes
Cardiac Myocytes
Genes
Extracellular Matrix
Homeostasis
Transcription Factors
Cytokines
Inflammation
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Khalil, H., Kanisicak, O., Prasad, V., Correll, R. N., Fu, X., Schips, T., ... Molkentin, J. D. (2017). Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. Journal of Clinical Investigation, 127(10), 3770-3783. https://doi.org/10.1172/JCI94753

Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. / Khalil, Hadi; Kanisicak, Onur; Prasad, Vikram; Correll, Robert N.; Fu, Xing; Schips, Tobias; Vagnozzi, Ronald J.; Liu, Ruijie; Huynh, Thanh; Lee, Se Jin; Karch, Jason; Molkentin, Jeffery D.

In: Journal of Clinical Investigation, Vol. 127, No. 10, 02.10.2017, p. 3770-3783.

Research output: Contribution to journalArticle

Khalil, H, Kanisicak, O, Prasad, V, Correll, RN, Fu, X, Schips, T, Vagnozzi, RJ, Liu, R, Huynh, T, Lee, SJ, Karch, J & Molkentin, JD 2017, 'Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis', Journal of Clinical Investigation, vol. 127, no. 10, pp. 3770-3783. https://doi.org/10.1172/JCI94753
Khalil H, Kanisicak O, Prasad V, Correll RN, Fu X, Schips T et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. Journal of Clinical Investigation. 2017 Oct 2;127(10):3770-3783. https://doi.org/10.1172/JCI94753
Khalil, Hadi ; Kanisicak, Onur ; Prasad, Vikram ; Correll, Robert N. ; Fu, Xing ; Schips, Tobias ; Vagnozzi, Ronald J. ; Liu, Ruijie ; Huynh, Thanh ; Lee, Se Jin ; Karch, Jason ; Molkentin, Jeffery D. / Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 10. pp. 3770-3783.
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