Cited by 302Inflammasome and immune disordersAtherosclerosis and Cardiovascular DiseasesNitric Oxide and Endothelin Effects

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Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

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Boini, Krishna M., Hussain, Tahir, Li, Pin-Lan, Koka, Sai S·2017·Cellular Physiology and Biochemistry

DOI 10.1159/000484623PMC PMC5828122

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Abstract

BACKGROUND/AIM: Plasma trimethylamine-N-oxide (TMAO), a product of intestinal microbial metabolism of dietary phosphatidylcholine has been recently associated with atherosclerosis and increased risk of cardiovascular diseases (CVD) in rodents and humans. However, the molecular mechanisms of how TMAO induces atherosclerosis and CVD progression are still unclear. The present study tested whether TMAO induces NLRP3 inflammasome formation and activation and thereby contributes to endothelial injury initiating atherogenesis. METHODS: Inflammasome formation and activation was determined by confocal microscopy, caspase-1 activity was measured by colorimetric assay, IL-1β production was measured using ELISA, cell permeability was determined by microplate reader and ZO-1 expression was determined by western blot analysis and confocal microscopy. In in vivo experiments, TMAO was infused by osmotic pump implantation. RESULTS: TMAO treatment significantly increased the colocalization of NLRP3 with Asc or NLRP3 with caspase-1, caspase-1 activity, IL-1β production, cell permeability in carotid artery endothelial cells (CAECs) compared to control cells. Pretreatment with caspase-1 inhibitor, WEHD or Nlrp3 siRNA abolished the TMAO-induced inflammasome formation, activation and cell permeability in these cells. In addition, we explored the mechanisms by which TMAO activates NLRP3 inflammasomes. TMAO-induced the activation of NLRP3 inflammasomes was associated with both redox regulation and lysosomal dysfunction. In animal experiments, direct infusion of TMAO in mice with partially ligated carotid artery were found to have increased NLRP3 inflammasome formation and IL-1β production in the intima of wild type mice. CONCLUSION: The formation and activation of NLRP3 inflammasomes by TMAO may be an important initiating mechanism to turn on the endothelial inflammatory response leading to endothelial dysfunction.

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Authors: Boini, K. M., Hussain, T., Li, P.-L., & Koka, S. S.
Affiliations: University of Houston (US)
Virginia Commonwealth University (US)
ORCID: Boini, Krishna M.
Hussain, Tahir
Li, Pin-Lan
Venue: Cellular Physiology and Biochemistry
Publisher: S. Karger AG
Published: 2017
Volume: 44
Issue: 1
Pages: 152-162
ISSN: 1015-8987 (ISSN-L)
1421-9778
DOI: 10.1159/000484623
PMC: PMC5828122
OpenAlex: W2767806634
Semantic Scholar: de8ac468d4e798c06de304d9dfc8cf3df3a51462
Cited by: 302
References: 60
Citations by year: 2026: 38 · 2025: 38 · 2024: 38 · 2023: 46 · 2022: 38 · 2021: 39 · 2020: 26 · 2019: 25 · 2018: 13 · 2017: 1
FWCI: 7.26
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
creativecommons.org/licenses/by-nc-nd/4.0/ (tdm)
Locations: Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (R01HL075316, R01HL057244)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104031)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Keywords: trimethylamine N-oxide, NLRP3 inflammasome, endothelial dysfunction, atherosclerosis, caspase-1, IL-1β, endothelial permeability, redox regulation, lysosomal dysfunction, cardiovascular disease, gut microbiota
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Amino Acid Chloromethyl Ketones, Animals, Carotid Arteries, Cells, Cultured, Male, Methylamines, Mice, Inbred C57BL, Microscopy, Fluorescence, Permeability, Signal Transduction, Caspase 1, RNA Interference, RNA, Small Interfering, Endothelial Cells, Mice, Interleukin-1beta, Inflammasomes, Caspase Inhibitors

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Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

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