Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis
Top Cited Papers
- 11 September 2017
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 127 (10), 3770-3783
- https://doi.org/10.1172/jci94753
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.Keywords
This publication has 61 references indexed in Scilit:
- Caspase-3 Protects Stressed Organs against Cell DeathMolecular and Cellular Biology, 2012
- Efficient inducible Cre‐mediated recombination in Tcf21cell lineages in the heart and kidneygenesis, 2011
- Transforming growth factor (TGF)-β signaling in cardiac remodelingJournal of Molecular and Cellular Cardiology, 2010
- The extracellular matrix: At the center of it allJournal of Molecular and Cellular Cardiology, 2010
- Origin of Cardiac Fibroblasts and the Role of PeriostinCirculation Research, 2009
- Adaptive and Maladptive Effects of SMAD3 Signaling in the Adult Heart After Hemodynamic Pressure OverloadingCirculation: Heart Failure, 2009
- Cellular and molecular mechanisms of fibrosisThe Journal of Pathology, 2007
- Genetic Manipulation of Periostin Expression Reveals a Role in Cardiac Hypertrophy and Ventricular RemodelingCirculation Research, 2007
- The role of TGF-β signaling in myocardial infarction and cardiac remodelingCardiovascular Research, 2007
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003