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J Am Coll Cardiol, 2005; 45:1018-1024, doi:10.1016/j.jacc.2004.12.065
© 2005 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: ATHEROSCLEROSIS

The involvement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in atherosclerosis

Yoav Michowitz, MD*, Emil Goldstein, MD*, Arie Roth, MD*, Arnon Afek, MD*, Anastasia Abashidze, BSc*, Yanai Ben Gal, MD{dagger}, Gad Keren, MD, FACC* and Jacob George, MD*,*

* Department of Cardiology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
{dagger} Department of Cardiothoracic Surgery, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Manuscript received October 15, 2004; revised manuscript received November 26, 2004, accepted December 6, 2004.

* Reprint requests and correspondence: Dr. Jacob George, Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (Email: jacobg{at}post.tau.ac.il).

OBJECTIVES: Herein, we determined the significance of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in atherosclerotic vascular disease.

BACKGROUND: Inflammation is associated with the pathogenesis of atherosclerosis. The TNF-related apoptosis-inducing ligand/APO-2L, a member of the TNF superfamily, has a role in apoptosis induction and is recognized for its immunomodulatory properties.

METHODS: Stable and vulnerable atherosclerotic human plaques and aortas from atherosclerotic mice were assayed for the presence of TRAIL, and its inducibility was assayed by immunoblot and real-time polymerase chain reaction on peripheral mononuclear cells incubated with oxidized low-density lipoprotein (oxLDL). Enzyme-linked immunosorbent assay was used for the determination of soluble TRAIL levels in atherosclerotic patients.

RESULTS: Tumor necrosis factor-related apoptosis-inducing ligand is present in stable atherosclerotic lesions, is increased in vulnerable plaques, and is found to colocalize with CD3 cells and oxLDL. The TNF-related apoptosis-inducing ligand messenger ribonucleic acid (mRNA) and protein expression was up-regulated in peripheral blood mononuclear cells after incubation with oxLDL. Serum levels of soluble TRAIL but not TNF-alpha or Fas-ligand were reduced significantly in patients with unstable angina as compared with patients with stable atherosclerotic disease and healthy subjects. A negative correlation was demonstrated between soluble TRAIL and C-reactive protein levels but not with levels of mRNA of TRAIL in peripheral blood mononuclear cells.

CONCLUSIONS: Tumor necrosis factor-related apoptosis-inducing ligand is expressed in plaque-infiltrating CD3 cells and induced by oxLDL, whereas levels of soluble TRAIL are reduced in patients with acute coronary syndromes and negatively correlate with C-reactive protein levels. These results support a possible role for TRAIL in atherosclerosis.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  CRP = C-reactive protein
  hsCRP = high-sensitivity C-reactive protein
  LPC = lysophosphatidylcholine
  oxLDL = oxidized low-density lipoprotein
  mRNA = messenger ribonucleic acid
  NCA = normal coronary arteries
  PBMCs = peripheral blood mononuclear cells
  RT-PCR = reverse-transcription polymerase chain reaction
  TNF = tumor necrosis factor
  TRAIL = tumor necrosis factor-related apoptosis-inducing ligand




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