Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction
Open accessAbstract
Rationale: Cardiac fibroblasts are key effector cells in the pathogenesis of cardiac fibrosis. Transforming growth factor (TGF)-β/Smad3 signaling is activated in the border zone of healing infarcts and induces fibrotic remodeling of the infarcted ventricle contributing to the development of diastolic dysfunction. Objective: The present study explores the mechanisms responsible for the fibrogenic effects of Smad3 by dissecting its role in modulating cardiac fibroblast phenotype and function. Methods and Results: Smad3 null mice and corresponding wild-type controls underwent reperfused myocardial infarction protocols. Surprisingly, reduced collagen deposition in Smad3−/− infarcts was associated with increased infiltration with myofibroblasts. In vitro studies demonstrated that TGF-β1 inhibited murine cardiac fibroblast proliferation; these antiproliferative effects were mediated via Smad3. Smad3−/− fibroblasts were functionally defective, exhibiting impaired collagen lattice contraction when compared with wild-type cells. Decreased contractile function was associated with attenuated TGF-β–induced expression of α-smooth muscle actin. In addition, Smad3−/− fibroblasts had decreased migratory activity on stimulation with serum, and exhibited attenuated TGF-β1–induced upregulation of extracellular matrix protein synthesis. Upregulation of connective tissue growth factor, an essential downstream mediator in TGF-β–induced fibrosis, was in part dependent on Smad3. Connective tissue growth factor stimulation enhanced extracellular matrix protein expression by cardiac fibroblasts in a Smad3-independent manner. Conclusions: Disruption of Smad3 results in infiltration of the infarct with abundant hypofunctional fibroblasts that exhibit impaired myofibroblast transdifferentiation, reduced migratory potential, and suppressed expression of fibrosis-associated genes.
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Overexpression of SMAD3 enhances, whereas knockdown inhibits αSMA and extracellular matrix production in fibroblasts; fibroblast-specific deletion of SMAD3 reduces αSMA production and myofibroblast phenotype.
“Overexpression of SMAD3 enhances, whereas knockdown inhibits αSMA and extracellular matrix production in fibroblasts (45–48). Furthermore, fibroblast-specific deletion of SMAD3 reduces αSMA production and myofibroblast phenotype (49–52), for example, loss of SMAD3 lowers the number of activated myofibroblasts in cardiac fibrosis in vivo and reduces extracellular matrix production by myofibroblasts”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [48]
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- Authors
- Dobaczewski, M., Bujak, M., Li, N., Gonzalez-Quesada, C., Mendoza, L. H., Wang, X.-F., & Frangogiannis, N. G.
- Affiliations
- Duke University (US)
- From the Section of Cardiovascular Sciences (M.D., M.B., N.L., C.G.-Q., L.H.M., N.G.F.), Department of Medicine, Baylor College of Medicine, Houston, Tex; and the Department of Pharmacology and Cancer Biology (X.-F.W.), Duke University Medical Center, Durham, NC.
- Venue
- Circulation Research
- Published
- 2010-08-06
- Volume
- 107
- Issue
- 3
- Pages
- 418-428
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC2917472
- OpenAlex
- W2167721417
- Cited by
- 385
- References
- 40
- Citations by year
- 2026: 21 · 2025: 16 · 2024: 27 · 2023: 23 · 2022: 29 · 2021: 33 · 2020: 22 · 2019: 27 · 2018: 28 · 2017: 36 · 2016: 18 · 2015: 29 · 2014: 19 · 2013: 27 · 2012: 20
- FWCI
- 12.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL-76246, R01 HL85440, R01HL085440, R01HL076246)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Smad3, TGF-beta signaling, cardiac fibroblasts, myocardial fibrosis, myofibroblast transdifferentiation, fibroblast proliferation, collagen deposition, alpha-smooth muscle actin, connective tissue growth factor, extracellular matrix, fibroblast migration, diastolic dysfunction
- MeSH terms
- Animals, Cell Differentiation, Cell Division, Cell Movement, Fibroblasts, Myocardial Contraction, Myocardial Infarction, Phenotype, Wound Healing, Trans-Activators, Up-Regulation, Extracellular Matrix Proteins, Mice, Knockout, Mice, Smad3 Protein, Transforming Growth Factor beta1
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