The shift of macrophages toward M1 phenotype promotes aortic valvular calcification
Open accessAbstract
Objective The purpose of the present study was to comprehensively compare the phenotype profile of infiltrated macrophages in human noncalcified and calcific aortic valves, and to determine whether the shift of macrophage polarization modulates valvular calcification in vitro.Methods Cell surface markers of macrophages and inflammatory cytokines expression in 90 cases of human noncalcified and calcific aortic valve leaflets were analyzed. The normal aortic valve interstitial cells were isolated and cultured in vitro. After incubation with nonconditioned medium and conditioned medium from unstimulated or lipopolysaccharide-stimulated U937 monocytes, valve interstitial cells were evaluated by osteogenic differentiation markers.Results Infiltration of macrophages was enhanced in the calcific aortic valves, and M1 phenotype was the predominant macrophage subsets. In addition, both proinflammatory and anti-inflammatory cytokines were significantly upregulated in the calcific aortic valves. Furthermore, lipopolysaccharide-stimulated monocytes presented with increased expression of inducible nitric oxide synthase and high proportional CD11c-positive (M1) macrophages. Conditioned medium from unstimulated monocytes promoted the osteogenic differentiation of valve interstitial cells in vitro, as evidenced by increased markers such as bone morphogenetic protein 2, osteopontin, and alkaline phosphatase. Conditioned medium from M1 macrophages further enhanced valve interstitial cells calcification. Enzyme-linked immunosorbent assay showed that M1 phenotype macrophages secreted tumor necrosis factors α and interleukin 6, and neutralizing antibodies to these 2 proinflammatory cytokines attenuated induction of osteogenic differentiation and calcification by the conditioned media.Conclusions Both total numbers and polarization of macrophage influence the process of calcification in human aortic valve. The shift toward M1 phenotype might promote valve interstitial cell calcification.
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Previous evidence suggests a bidirectional crosstalk between M1 macrophages and valve interstitial cells, promoting inflammation and fibrosis during early stages of CAVS.
“Moreover, previous evidence suggests a bidirectional crosstalk between M1 macrophages and valve interstitial cells, promoting inflammation and fibrosis during early stages of CAVS.44,55”
From Transcriptomic signatures of calcific aortic valve stenosis severity in human tricuspid and bicuspid aortic valves (2025) · cites this paper as [55]
The results are consistent with previous studies showing a larger number of activated proinflammatory macrophages (M1) in calcified vs noncalcified valves.
“The results are consistent with previous studies showing a larger number of activated proinflammatory macrophages (M1) in calcified vs noncalcified valves.55”
From Transcriptomic signatures of calcific aortic valve stenosis severity in human tricuspid and bicuspid aortic valves (2025) · cites this paper as [55]
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- Authors
- Li, G., Qiao, W., Zhang, W., Li, F., Shi, J., & Dong, N.
- Affiliations
- Wuhan Union Hospital (CN)
- Corresponding author
- Shi, Jiawei
- Dong, Nianguo
- Venue
- The Journal of Thoracic and Cardiovascular Surgery
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 153
- Issue
- 6
- Pages
- 1318-1327.e1
- ISSN
- 0022-5223 (ISSN-L)
- OpenAlex
- W2586468746
- Cited by
- 118
- References
- 32
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 11 · 2023: 19 · 2022: 18 · 2021: 15 · 2020: 22 · 2019: 8 · 2018: 5 · 2017: 3
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic and Cardiovascular Surgery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation (81270297, 81300175)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- aortic valve calcification, macrophage polarization, M1 macrophage phenotype, valvular interstitial cells, osteogenic differentiation, inflammatory cytokines, TNF-α, interleukin-6, inducible nitric oxide synthase, BMP-2, osteopontin, calcific aortic valve disease
- MeSH terms
- Cell Plasticity, Alkaline Phosphatase, Aortic Valve, Calcinosis, Cell Differentiation, Humans, Macrophages, Monocytes, Osteogenesis, Phenotype, Biomarkers, Case-Control Studies, Cytokines, Culture Media, Conditioned, Inflammation Mediators, Paracrine Communication, U937 Cells, Osteopontin, Bone Morphogenetic Protein 2
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