ArticleThe Journal of clinical investigation2017
Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 575 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
575 citing papers in PubMed, 1 synthesis or guideline pooled it, 880 citations in OpenAlex.
- Fighting Bleb Fibrosis After Glaucoma Surgery: Updated Focus on Key Players and Novel Targets for Therapy.International journal of molecular sciences · 2025Pooled it
- Integration of Collaborative Cross and Hybrid Mouse Diversity Panel studies does not significantly improve genome wide association study results.BMC research notes · 2026Article
- Roles of inflammation and metabolic dysfunction in cardiovascular diseases: molecular mechanisms and therapeutic targets.Molecular biomedicine · 2026Review
- Collagen Prolyl 4-Hydroxylase: An Emerging Key Player in Cardiac Fibrosis.Journal of cardiovascular translational research · 2026Review
- Spatiotemporal Nanotherapy After Myocardial Infarction: Targeting the Inflammatory-to-reparative Transition With Extracellular Vesicles and Engineered Nanoparticles.Cardiovascular drugs and therapy · 2026Review
- Biomechanical stress unmasks a fibroblast-dependent hypercontractile-disarray phenotype in MYBPC3 truncation HCM.APL bioengineering · 2026Article
- Branched-chain amino acid transaminase 1-mediated pathway promotes proline-dependent collagen production in cardiac myofibroblasts.The Journal of clinical investigation · 2026Article
- Role of ATOH8 in Mitigating Cardiac Fibrosis in Heart Failure via Inhibition of the Transcriptional Repression of Smad7 by RUNX2.Biomolecules & therapeutics · 2026Article
- Exosome-Mediated Systemic Signaling: Mechanisms, Disease Integration, and Translational Potential.Current issues in molecular biology · 2026Review
- Genome folding and nuclear speckles converge to orchestrate fibroblast activation.Science advances · 2026Article
- Natural Products Targeting Myocardial Fibrosis: Pharmacological Basis, Molecular Mechanisms and Translational Barriers.International journal of molecular sciences · 2026Review
- Selective expansion of cardiac macrophage subtypes distinguishes their functional roles in disease and homeostasis.The Journal of clinical investigation · 2026Article
- First Insights on the Upcoming Role of Next-Generation PLLA-LASYNPRO in Aesthetic and Regenerative Medicine: A Survey of Experts-the PLLA-LASYNPRO Rationale.Facial plastic surgery : FPS · 2026Article
- An Integrated Therapeutic Strategy for Cardiorenal Syndrome to Target Oxidative Stress, Inflammation, and Fibrosis.Reviews in cardiovascular medicine · 2026Review
- The cardiac 4D nucleome: nuclear and chromatin dynamics across development, disease and ageing.Nature reviews. Cardiology · 2026Review
- Ubiquitin-Related Proteostatic Programs in Cycling Fibroblast-Lineage Remodeling After Myocardial Ischemic Injury: A Hypothesis Informed by Single-Cell and Spatial Transcriptomics.International journal of molecular sciences · 2026Review
- Inflammatory and hormonal crosstalk linking rheumatic fever to chronic valvular heart disease.Molecular biology reports · 2026Review
- Macrophage-Dependent Intercellular Crosstalk in Multiphenotypic Heart Failure With Preserved Ejection Fraction.Journal of the American Heart Association · 2026Review
- Cardiomyocyte-Specific Smad7 Protects the Pressure-Overloaded Heart, Inhibiting the Transforming Growth Factor-β Receptor 1/Smad2/3 Cascade.Journal of the American Heart Association · 2026Article
- Article
515 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.