Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans
Open accessAbstract
Objective Calcific aortic valve disease is a progressive condition that shares some common pathogenic features with atherosclerosis. Transforming growth factor-β1 is a recognized mediator of atherosclerosis and is expressed in aortic valve lesions. Transforming growth factorβ1 stimulates glycosaminoglycan elongation of proteoglycans that is associated with increased lipid binding. We investigated the presence of transforming growth factor-β1 and downstream signaling intermediates in diseased human aortic valves and the effects of activated transforming growth factor-β1 receptor signaling on aortic valve interstitial cell proteoglycan synthesis and lipid binding as a possible mechanism for the initiation of the early lesion of calcific aortic valve disease.Methods and results Diseased human aortic valve leaflets demonstrated strong immunohistochemical staining for transforming growth factor-β1 and phosphorylated Smad2/3. In primary porcine aortic valve interstitial cells, Western blots showed that transforming growth factor-β1 stimulated phosphorylation in both the carboxy and linker regions of Smad2/3, which was inhibited by the transforming growth factor-β1 receptor inhibitor SB431542. Gel electrophoresis and size exclusion chromatography demonstrated that SB431542 decreased transforming growth factor-β1-mediated [(35)S]-sulfate incorporation into proteoglycans in a dose-dependent manner. Further, in proteoglycans derived from transforming growth factor-β1-treated valve interstitial cells, gel mobility shift assays demonstrated that inhibition of transforming growth factor-β1 receptor signaling resulted in decreased lipid binding.Conclusions Classic transforming growth factor-β1 signaling is present in human aortic valves in vivo and contributes to the modification of proteoglycans expressed by valve interstitial cells in vitro. These findings suggest that transforming growth factor-β1 may promote increased low-density lipoprotein binding in the early phases of calcific aortic valve disease.
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Transforming growth factor β-1, which is activated in calcific aortic stenosis, promotes elongation of glycosaminoglycan chains.
“Moreover, transforming growth factor β-1 (TGF-β1), which is activated in calcific AS, has been shown to promote the elongation of glycosaminoglycan (GAG) chains55.”
From Calcific aortic stenosis (2016) · cites this paper as [55]
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- Authors
- Osman, N., Grande-Allen, K. J., Ballinger, M. L., Getachew, R., Marasco, S., O'Brien, K. D., & Little, P. J.
- Affiliations
- The Alfred Hospital (AU)
- Rice University (US)
- Baker Heart and Diabetes Institute (AU)
- RMIT University (AU)
- Corresponding author
- Osman, Narin
- Venue
- Cardiovascular Pathology
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 22
- Issue
- 2
- Pages
- 146-155
- ISSN
- 1054-8807 (ISSN-L)
- PMC
- PMC10584518
- OpenAlex
- W2074237229
- Cited by
- 32
- References
- 65
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 1
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cardiovascular Pathology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rice Research Repository (Rice University) (acceptedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Rice Research Repository (Rice University) (submittedVersion)
- Funders
- Diabetes Australia Research Trust
- Diabetes Australia
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL071739, HL071739)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Keywords
- calcific aortic valve disease, TGF-β1, Smad2/3 signaling, proteoglycans, aortic valve interstitial cells, low-density lipoprotein binding, lipid binding, valve calcification, SB431542, TGF-β receptor inhibition
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Animals, Aortic Valve, Benzamides, Cells, Cultured, Dioxoles, Glycosaminoglycans, Heart Valve Diseases, Humans, Lipoproteins, LDL, Phosphorylation, Proteoglycans, Swine, Signal Transduction, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta1
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