Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 10, Pages 3770-3783Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI94753
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Funding
- NIH [R01AR060636]
- Howard Hughes Medical Institute
- Swiss National Science Foundation [P2LAP3_148429, P300P3_158486]
- NIH
- Swiss National Science Foundation (SNF) [P300P3_158486, P2LAP3_148429] Funding Source: Swiss National Science Foundation (SNF)
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The master cytokine TGF-beta mediates tissue fibrosis associated with inflammation and tissue injury. TGF-beta induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-beta signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-beta-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-beta 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-beta 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-beta Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.
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