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Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway
Abstract
Background Many studies have identified trimethylamine N-oxide (TMAO) as a new risk factor of cardiovascular diseases. It has been suggested that TMAO promotes atherosclerosis development. However, the underlying mechanism is still unclear.Methods Apoe-/- mice were fed a high-fat diet and given water with or without TMAO for 8-week. Histological and immunohistological analyses were used to evaluate the atherogenic effect of TMAO in vivo. We also employed peritoneal elicited macrophages and RAW264.7 to assess the role of MAPK/JNK pathway in TMAO-induced formation of foam cells.Results TMAO significantly promoted plaque progression in apoe-/- mice fed with high-fat diet for 8 weeks. Besides, macrophage recruitment, CD36 and proinflammatory cytokine expressions were enhanced by TMAO in plaque lesions. In vitro, TMAO increased the macrophage migration and the expression of TNF-α, IL-6 and ICAM1. In addition, CD36 expression and foam cell formation induced by ox-LDL were also enhanced by TMAO, which could be attenuated by siRNA-mediated knockdown of CD36. We additionally used MAPK inhibitor (SB230580) and JNK inhibitor (SP600125) to assess the MAPK/JNK pathway in TMAO-induced CD36 expression. Western blotting showed that both SB230580 and SP600125 could reduce the expression of CD36 induced by ox-LDL and TMAO. Moreover, SB230580 and SP600125 could also reduce the formation of foam cells.Conclusions TMAO promotes the atherosclerosis in vivo and in vitro.CD36/MAPK/JNK pathway may play a crucial role in TMAO-induced formation of foam cells.
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“studies suggesting an association between high plasma TMAO levels and risk for developing atherosclerosis have increased markedly [7,13,14,15,16,17]”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [13]
In the citing paper
“MAPK/JNK pathway seems to play a critical role in TMAO-induced atherosclerosis since, when SB230580 (a MAPK inhibitor) and SP600125 (a JNK inhibitor) were used, foam cell formation and CD36 expression were reduced. Foam cell formation was also attenuated by the use of siRNA-mediated knockdown of CD36 [13].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [13]
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Metadata
- Authors
- Geng, J., Yang, C., Wang, B., Zhang, X., Hu, T., Gu, Y., & Li, J.
- Affiliations
- Huaian First People’s Hospital (CN)
- Corresponding author
- Li, Ju
- Venue
- Biomedicine & Pharmacotherapy
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 97
- Pages
- 941-947
- ISSN
- 0753-3322 (ISSN-L)
- OpenAlex
- W2767697969
- Cited by
- 297
- References
- 30
- Citations by year
- 2026: 26 · 2025: 31 · 2024: 35 · 2023: 59 · 2022: 54 · 2021: 40 · 2020: 23 · 2019: 18 · 2018: 11
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biomedicine & Pharmacotherapy (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Jiangsu Province Qing Nian Ren Cai (QNRC2016432)
- Huai’an Science Support Project (HASZ2013030)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- trimethylamine N-oxide, atherosclerosis, CD36, foam cell formation, macrophage recruitment, macrophage migration, oxidized LDL, inflammatory cytokines, ICAM-1, plaque progression, ApoE-deficient mice, high-fat diet, cardiovascular risk factors
- MeSH terms
- RAW 264.7 Cells, Animals, Apolipoproteins E, Disease Models, Animal, Foam Cells, Lipoproteins, LDL, Macrophages, Male, Methylamines, Mice, Inbred C57BL, Cytokines, Macrophages, Peritoneal, Mice, Knockout, Disease Progression, CD36 Antigens, MAP Kinase Signaling System, Atherosclerosis, Mice, Gene Knockdown Techniques, Plaque, Atherosclerotic
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