MicroRNA-23 Restricts Cardiac Valve Formation by Inhibiting Has2 and Extracellular Hyaluronic Acid Production
Open accessAbstract
Rationale: Since their discovery almost 20 years ago, microRNAs have been shown to perform essential roles during tissue development and disease. Although roles for microRNAs in the myocardium during embryo development and cardiac disease have been demonstrated, very little is know about their role in the endocardium or during cardiac valve formation. Objective: To study the role of microRNAs in cardiac valve formation. Methods and Results: We show that zebrafish dicer mutant embryos, lacking mature miRNAs, form excessive endocardial cushions. By screening miRNAs expressed in the heart, we found that miR-23 is both necessary and sufficient for restricting the number of endocardial cells that differentiate into endocardial cushion cells. In addition, in mouse endothelial cells, miR-23 inhibited a transforming growth factor-β–induced endothelial-to-mesenchymal transition. By in silico screening of expression data with predicted miR-23 target sites combined with in vivo testing, we identified hyaluronic acid synthase 2 ( Has2) , Icat , and Tmem2 as novel direct targets of miR-23. Finally, we demonstrate that the upregulation of Has2 , an extracellular remodeling enzyme required for endocardial cushion and valve formation, is responsible for the excessive endocardial cushion cell differentiation in dicer mutants. Conclusions: MiR-23 in the embryonic heart is required to restrict endocardial cushion formation by inhibiting Has2 expression and extracellular hyaluronic acid production.
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miR-23 is involved in regulating cardiac development in several species such as zebrafish, mice, and chickens.
“miR-23 is involved in regulating the cardiac development in several species such as zebrafish, mice, and chickens.”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [120]
The Loss of MiR-23 Results in Enhanced EC Formation section reports cardiac defects after miR-23 knockdown in zebrafish. The mouse endothelial-cell section shows that miR-23 inhibits a process involved in valve formation in cultured mouse cells, but its mention of chick embryos concerns that process, not miR-23. The paper therefore does not establish miR-23’s role in cardiac development in chickens. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn zebrafish and mice, miR-23 within the embryonic heart is essential to confine endocardial cushion formation by inhibiting Has2 and extracellular hyaluronic acid production.
“In zebrafish and mice, miR-23 within the embryonic heart is essential to confine endocardial cushion formation by inhibiting the expression of hyaluronic acid synthase 2 (Has2) and extracellular hyaluronic acid production.”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [120]
The Discussion (page unavailable) concludes that miR-23 restricts endocardial cushion formation in zebrafish by limiting Has2 expression and hyaluronic acid production. The mouse experiments instead used cultured embryonic endothelial cells and showed inhibition of TGF-β-induced endothelial-to-mesenchymal transition; they did not establish that miR-23 is essential for confining cushion formation in mouse embryonic hearts. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn chickens and mice, over-expression of miR-23 during the early stages of myocardial formation hinders the generation of myocardium in the epicardial/transverse membrane.
“Further evidence from chickens and mice has indicated that the over-expression of miR-23 during the early stages of myocardial formation hinders the generation of myocardium in the epicardial/transverse membrane [120,121].”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [120]
The section 'Reexpressing MiR-23 Rescues Ectopic EC Differentiation in MZdicer Mutants' reports that added miR-23 restricts endocardial cushion differentiation in zebrafish; the Discussion reports inhibition of endothelial-to-mesenchymal transition in mouse cells. Neither passage establishes that overexpression hinders myocardium generation in chickens or mice, or addresses the claimed epicardial/transverse membrane site. The 'Loss of MiR-23 Results in Enhanced EC Formation' section also reports normal myocardial patterning after miR-23 loss. Page numbers were not available in our copy. (LLM, conf=0.83)
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- Authors
- Lagendijk, A. K., Goumans, M. J., Burkhard, S. B., & Bakkers, J.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- From the Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (A.K.L., S.B.B., J.B.); the Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands (M.J.G.); and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.B.).
- Venue
- Circulation Research
- Published
- 2011-09-02
- Volume
- 109
- Issue
- 6
- Pages
- 649-657
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2150369823
- Cited by
- 119
- References
- 31
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 6 · 2023: 2 · 2022: 6 · 2021: 5 · 2020: 2 · 2019: 15 · 2018: 12 · 2017: 6 · 2016: 9 · 2015: 9 · 2014: 10 · 2013: 15 · 2012: 10
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion, cc-by-nc-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion, cc-by-nc-sa)
- Funders
- Koninklijke Nederlandse Akademie van Wetenschappen
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Directorate for Biological Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- endocardial cushion, hyaluronic acid, endothelial-to-mesenchymal transition, zebrafish, miRNA target genes, ICAT, TMEM2, embryonic heart development
- MeSH terms
- Hyaluronan Synthases, Animals, Cell Count, Cell Differentiation, Cells, Cultured, Heart Valves, Hyaluronic Acid, Glucuronosyltransferase, Zebrafish, Zebrafish Proteins, Animals, Genetically Modified, MicroRNAs, Extracellular Fluid, Mice, Endocardial Cushions
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