Twist1 promotes heart valve cell proliferation and extracellular matrix gene expression during development in vivo and is expressed in human diseased aortic valves
Open accessAbstract
During embryogenesis the heart valves develop from undifferentiated mesenchymal endocardial cushions (EC), and activated interstitial cells of adult diseased valves share characteristics of embryonic valve progenitors. Twist1, a class II basic-helix-loop-helix (bHLH) transcription factor, is expressed during early EC development and is down-regulated later during valve remodeling. The requirements for Twist1 down-regulation in the remodeling valves and the consequences of prolonged Twist1 activity were examined in transgenic mice with persistent expression of Twist1 in developing and mature valves. Persistent Twist1 expression in the remodeling valves leads to increased valve cell proliferation, increased expression of Tbx20, and increased extracellular matrix (ECM) gene expression, characteristic of early valve progenitors. Among the ECM genes predominant in the EC, Col2a1 was identified as a direct transcriptional target of Twist1. Increased Twist1 expression also leads to dysregulation of fibrillar collagen and periostin expression, as well as enlarged hypercellular valve leaflets prior to birth. In human diseased aortic valves, increased Twist1 expression and cell proliferation are observed adjacent to nodules of calcification. Overall, these data implicate Twist1 as a critical regulator of valve development and suggest that Twist1 influences ECM production and cell proliferation during disease.
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Persistent TWIST1 expression in valves increases cell proliferation, dysregulates fibrillary collagen, and leads to enlarged hypercellular valve leaflets in a mouse model; high TWIST1 expression was observed in human diseased aortic valves.
“Persistent expression in valves has been shown to increase cell proliferation, dysregulation of fibrillary collagen and lead to enlarged hypercellular valve leaflets in a mouse model. In the same study, high TWIST1 expression was observed in human diseased aortic valves23.”
From Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation (2024) · cites this paper as [23]
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- Authors
- Chakraborty, S., Wirrig, E. E., Hinton, R. B., Merrill, W. H., Spicer, D. B., & Yutzey, K. E.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- University of Cincinnati (US)
- Maine Medical Center Research Institute (US)
- Corresponding author
- Yutzey, Katherine E.
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 347
- Issue
- 1
- Pages
- 167-179
- ISSN
- 0012-1606 (ISSN-L)
- PMC
- PMC2950232
- OpenAlex
- W2100604248
- Cited by
- 92
- References
- 33
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 9 · 2023: 3 · 2022: 6 · 2021: 8 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 8 · 2015: 4 · 2014: 10 · 2013: 3 · 2012: 10
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association-Great Rivers Affiliate Post-Doctoral Fellowship (0825627D)
- NIH (HL085122, HL082716, HL094319)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TWIST1, heart valve development, endocardial cushion, extracellular matrix gene expression, aortic valve disease, valve calcification, Tbx20, COL2A1, periostin, fibrillar collagen, bHLH transcription factors, valve remodeling, transgenic mice
- MeSH terms
- Animals, Animals, Newborn, Base Sequence, Calcinosis, Extracellular Matrix, Heart Valve Diseases, Heart Valves, Humans, Introns, Molecular Sequence Data, Morphogenesis, Cardiomyopathies, Nuclear Proteins, Protein Binding, Regulatory Sequences, Nucleic Acid, Biomarkers, Gene Expression Regulation, Developmental, Receptor Protein-Tyrosine Kinases, T-Box Domain Proteins, Collagen Type II, Receptor, TIE-2, Cell Proliferation, Mice, Twist-Related Protein 1
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