Journal Article

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

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

2017

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adenoviruses / Animals / Apoptosis / Biomedical research / Cardiomyocytes / Clonal deletion / Cytokines / Disease / Extracellular matrix / Fibroblasts / Fibrosis / Gene Deletion / Gene expression / Genetic engineering / Growth factors / Heart attacks / Heart diseases / Heart Diseases - genetics / Heart Diseases - metabolism / Heart Diseases - pathology / Heart failure / Homeostasis / Kinases / Latency / Male / Mice / Mice, Transgenic / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Myofibroblasts - metabolism / Myofibroblasts - pathology / Organ Specificity / Phosphorylation / Pressure / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Proteins / Receptors, Transforming Growth Factor beta - genetics / Receptors, Transforming Growth Factor beta - metabolism / Rodents / Signal Transduction / Smad2 protein / Smad2 Protein - genetics / Smad2 Protein - metabolism / Smad3 protein / Smad3 Protein - genetics / Smad3 Protein - metabolism / Transcription factors / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - metabolism