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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, 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
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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