Cited by 297Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismNitric Oxide and Endothelin Effects

Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway

Geng, Jin, Yang, Chenchen, Wang, Bingjian, Zhang, Xiwen, Hu, Tingting, Gu, Yang, Li, Ju·2018·Biomedicine & Pharmacotherapy

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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Crossref · 10.1016/j.biopha.2017.11.016

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  • High plasma TMAO levels are associated with risk for developing atherosclerosis.

    “studies suggesting an association between high plasma TMAO levels and risk for developing atherosclerosis have increased markedly [7,13,14,15,16,17]”
  • The MAPK/JNK pathway plays a critical role in TMAO-induced atherosclerosis, as MAPK inhibitor SB230580 and JNK inhibitor SP600125 reduce foam cell formation and CD36 expression, and siRNA-mediated knockdown of CD36 attenuates foam cell formation.

    “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].”

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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
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
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Physiology › 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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