Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease
Open accessAbstract
Studies of human diseased aortic valves have demonstrated increased expression of genetic markers of valve progenitors and osteogenic differentiation associated with pathogenesis. Three potential mouse models of valve disease were examined for cellular pathology, morphology, and induction of valvulogenic, chondrogenic, and osteogenic markers. Osteogenesis imperfecta murine (Oim) mice, with a mutation in Col1a2, have distal leaflet thickening and increased proteoglycan composition characteristic of myxomatous valve disease. Periostin null mice also exhibit dysregulation of the ECM with thickening in the aortic midvalve region, but do not have an overall increase in valve leaflet surface area. Klotho null mice are a model for premature aging and exhibit calcific nodules in the aortic valve hinge-region, but do not exhibit leaflet thickening, ECM disorganization, or inflammation. Oim/oim mice have increased expression of valve progenitor markers Twist1, Col2a1, Mmp13, Sox9 and Hapln1, in addition to increased Col10a1 and Asporin expression, consistent with increased proteoglycan composition. Periostin null aortic valves exhibit relatively normal gene expression with slightly increased expression of Mmp13 and Hapln1. In contrast, Klotho null aortic valves have increased expression of Runx2, consistent with the calcified phenotype, in addition to increased expression of Sox9, Col10a1, and osteopontin. Together these studies demonstrate that oim/oim mice exhibit histological and molecular characteristics of myxomatous valve disease and Klotho null mice are a new model for calcific aortic valve disease.
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VICs are specialized cardiac fibroblasts, generally quiescent under homeostatic conditions, and their activation is associated with valve disease including calcification and regurgitation.
“VICs, which are specialized cardiac fibroblasts, are generally quiescent under homoeostatic conditions, and their activation is intimately associated with valve disease states, including calcification and regurgitation2,3.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [2]
The Results section (“VIC activation, cell proliferation, and cellularity”; page unavailable) reports little to no proliferation in normal adult valves and describes VIC activation in adult human calcific aortic valve disease. The Discussion links VIC activation to valve disease and a previously described calcification process. Our copy does not characterize VICs as specialized cardiac fibroblasts or link their activation specifically to regurgitation; it also finds no myofibroblast activation in the mouse models at the stages analyzed. (LLM, conf=0.87)
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Self-citationA calcified polymeric valve for valve-in-valve applications
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- Authors
- Cheek, J. D., Wirrig, E. E., Alfieri, C. M., James, J. F., & Yutzey, K. E.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Yutzey, Katherine E.
- Venue
- Journal of Molecular and Cellular Cardiology
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 52
- Issue
- 3
- Pages
- 689-700
- ISSN
- 0022-2828 (ISSN-L)
- PMC
- PMC3294059
- OpenAlex
- W2067062055
- Cited by
- 80
- References
- 62
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 2 · 2021: 9 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 9 · 2015: 10 · 2014: 8 · 2013: 3 · 2012: 3
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Molecular and Cellular Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL114682, R01HL094319, R01HL082716)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Keywords
- calcific aortic valve disease, osteogenic differentiation, chondrogenic differentiation, COL1A2 mutation, extracellular matrix, proteoglycans, Runx2, TWIST1, SOX9, HAPLN1, MMP-13, osteopontin, mouse model
- MeSH terms
- Klotho Proteins, Animals, Aortic Valve, Calcinosis, Connective Tissue Cells, Disease Models, Animal, Echocardiography, Glucuronidase, Heart Valve Diseases, Humans, Osteogenesis, Osteogenesis Imperfecta, Proteoglycans, Signal Transduction, Cell Adhesion Molecules, Mice, Knockout, Chondrogenesis, Protein Transport, Cell Proliferation, Mice
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