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Cited by 65Endoplasmic Reticulum Stress and DiseaseAtherosclerosis and Cardiovascular DiseasesCholesterol and Lipid Metabolism

Triglyceride-Rich Lipoprotein Modulates Endothelial Vascular Cell Adhesion Molecule (VCAM)-1 Expression via Differential Regulation of Endoplasmic Reticulum Stress

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Wang, Ying I., Bettaieb, Ahmed, Sun, Chongxiu, DeVerse, J. Sherrod, Radecke, Christopher E., Mathew, Steven, Edwards, Christina M., Haj, Fawaz G. +2 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0078322PMC PMC3804477
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Abstract

Circulating triglyceride-rich lipoproteins (TGRL) from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC), defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNFα) stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium. To establish how TGRL metabolism is linked to VCAM-1 regulation, we examined endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) pathways. Regardless of its atherogenicity, the rate and extent of TGRL internalization and lipid droplet formation by HAEC were uniform. However, pro-atherogenic TGRL exacerbated ER membrane expansion and stress following TNFα stimulation, whereas anti-atherogenic TGRL ameliorated such effects. Inhibition of ER stress with a chemical chaperone 4-phenylbutyric acid decreased TNFα-induced VCAM-1 expression and abrogated TGRL's atherogenic effect. Activation of ER stress sensors PKR-like ER-regulated kinase (PERK) and inositol requiring protein 1α (IRE1α), and downstream effectors including eukaryotic initiation factor-2α (eIF2α), spliced X-box-binding protein 1 (sXBP1) and C/EBP homologous protein (CHOP), directly correlated with the atherogenic activity of an individual's TGRL. Modulation of ER stress sensors also correlated with changes in expression of interferon regulatory factor 1 (IRF-1), a transcription factor of Vcam-1 responsible for regulation of its expression. Moreover, knockdown studies using siRNA defined a causal relationship between the PERK/eIF2α/CHOP pathway and IRF-1-mediated VCAM-1 expression. We conclude that ER stress and the UPR contribute to the regulation of Vcam-1 transcription as a function of the atherogenic nature of TGRL.

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  • TRL remnants contribute to a prothrombotic phenotype by promoting platelet activation and aggregation and modulating endothelial and systemic hemostatic responses.

    “In addition, TRL remnants contribute to a prothrombotic phenotype within the vascular wall by promoting platelet activation and aggregation, and by modulating both endothelial and systemic hemostatic responses [29–32].”

    From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [30]

    The Results and Discussion describe how postprandial triglyceride-rich lipoproteins alter VCAM-1 expression and inflammatory responses in human aortic endothelial cells; they do not address a prothrombotic phenotype. Searches for platelet activation, aggregation, coagulation, and endothelial or systemic hemostatic responses found no passage supporting the attributed claim. The passages have section labels but no page numbers. (LLM, conf=0.76)

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  • TRL remnants increase expression of plasminogen activator inhibitor-1 (PAI-1), impairing fibrinolytic activity, leading to reduced clot resolution and enhanced thrombus persistence.

    “Moreover, remnants have been shown to increase the expression of plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue plasminogen activator (tPA), thereby impairing fibrinolytic activity. Elevated PAI-1 levels lead to reduced clot resolution capacity and have been associated with enhanced thrombus persistence, particularly at sites of plaque disruption [29, 30].”

    From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [30]

    The Results sections on ER stress and VCAM-1 report how TGRL affects endothelial adhesion-molecule expression, not PAI-1 or fibrinolysis. Searches for PAI-1, plasminogen activator, clot resolution, and thrombus persistence found no passage addressing the attributed claim. Page numbers were not available in our copy. (LLM, conf=0.75)

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Research works printed but not linked: 37

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Authors
Wang, Y. I., Bettaieb, A., Sun, C., DeVerse, J. S., Radecke, C. E., Mathew, S., Edwards, C. M., Haj, F. G., Passerini, A. G., & Simon, S. I.
Affiliations
University of California, Davis (US)
Corresponding author
Simon, Scott I.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-10-21
Volume
8
Issue
10
Pages
e78322
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0078322
PMC
PMC3804477
OpenAlex
W2006998501
Cited by
65
References
41
Citations by year
2026: 1 · 2025: 5 · 2024: 7 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 3 · 2014: 5
FWCI
3.09
Type
journal article
Language
en
Update notices
expression_of_concern (2024-03-13)
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL082689, HL082689)
  • National Cancer Institute (P30CA093373)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090492)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
triglyceride-rich lipoproteins, VCAM-1, endoplasmic reticulum stress, unfolded protein response, atherosclerosis, endothelial inflammation, monocyte adhesion, IRF1, TNF-α, 4-phenylbutyric acid, postprandial lipemia, hypertriglyceridemia, sXBP1
MeSH terms
Cells, Cultured, Endoplasmic Reticulum, Endothelium, Vascular, Female, Gene Expression Regulation, Humans, Lipoproteins, Male, Monocytes, Triglycerides, Tumor Necrosis Factor-alpha, Down-Regulation, Up-Regulation, Vascular Cell Adhesion Molecule-1, Endothelial Cells, Atherosclerosis, Unfolded Protein Response, Endoplasmic Reticulum Stress

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