Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/– mice
Evis Harja, … , Shi Fang Yan, Ann Marie Schmidt
Evis Harja, … , Shi Fang Yan, Ann Marie Schmidt
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(1):183-194. https://doi.org/10.1172/JCI32703.
View: Text | PDF
Research Article Cardiology Article has an altmetric score of 3

Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/– mice

  • Text
  • PDF
Abstract

Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE–/– mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.

Authors

Evis Harja, De-xiu Bu, Barry I. Hudson, Jong Sun Chang, Xiaoping Shen, Kellie Hallam, Anastasia Z. Kalea, Yan Lu, Rosa H. Rosario, Sai Oruganti, Zana Nikolla, Dmitri Belov, Evanthia Lalla, Ravichandran Ramasamy, Shi Fang Yan, Ann Marie Schmidt

×

Figure 6

RAGE-mediated upregulation of inflammatory molecules in human aortic endothelial cells.

Options: View larger image (or click on image) Download as PowerPoint
RAGE-mediated upregulation of inflammatory molecules in human aortic end...
(A) Human aortic endothelial cells were subjected to lentiviral infection introducing full-length or DN-RAGE. Cells were exposed to S100b and permeability assay performed. *P < 0.0001 versus unstimulated full-length RAGE; **P < 0.0001 versus S100b-stimulated full-length RAGE. (B and C) Human endothelial cells were subjected to introduction of siRNA to reduce RAGE transcripts (B) and RAGE protein (C) without effect on GAPDH transcripts or protein. (D) Endothelial cells were subjected to RAGE or scramble siRNA and incubated with 10 μg/ml S100b for 4 hours. Western blotting was performed to probe VCAM-1 antigen and β-actin. *P < 0.0001. (E) Human aortic endothelial cells were stimulated with 10 μg/ml S100b for 20 minutes. Western blotting was performed to detect phospho/total-JNK MAP kinases. *P < 0.0001. (F) Endothelial cells were treated with JNK MAP kinase inhibitor SP60025 (10 μM) for 60 minutes followed by S100b (10 μg/ml) for 4 hours and Western blotting performed with anti–VCAM-1 IgG and anti–β-actin IgG. **P < 0.0001 versus S100b-stimulated, non–SP600125-treated. (G) oxLDL (5 μg/ml) was incubated with human aortic endothelial cells and Western blotting performed for detection of phospho/total-JNK MAP kinase. (H) Cells were treated with 10 μM SP600125 for 1 hour followed by incubation with oxLDL for 4 hours. Western blotting was performed for detection of VCAM-1 antigen. *P < 0.0001. (I) Cells were treated with siRNA to knock down JNK MAP kinase followed by incubation with oxLDL for 4 hours. Western blotting was performed for detection of VCAM-1 antigen. Where indicated by the white line, lanes were run on the same gel but were noncontiguous. *P < 0.05; **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 24 patents
131 readers on Mendeley
1 readers on CiteULike
See more details