Published Online
on January 22, 2004

A more recent version of this article appeared on February 1, 2004

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Submitted on September 24, 2003
Accepted on October 30, 2003

NF-B Activation and Fas Ligand Overexpression in Blood and Plaques of Patients With Carotid Atherosclerosis. Potential Implication in Plaque Instability

José Luis Martín-Ventura BS; Luis Miguel Blanco-Colio PhD; Begoña Muñoz-García BS; Almudena Gómez-Hernández BS; Ana Arribas MD; Luis Ortega MD; José Tuñón MD; and Jesús Egido MD^*

From the Vascular Research Laboratory (J.L.M.-V., L.M.B.-C., B.M.-G., A.G.-H., J.E.), Department of Vascular Surgery (A.A.), and Department of Cardiology (J.T.), Fundación Jiménez Díaz, Autonoma University, and Department of Pathology, Hospital Clínico San Carlos (L.O.), Madrid, Spain.

^* To whom correspondence should be addressed. E-mail: jegido{at}fjd.es.

Background and Purpose--Apoptosis is present in human atherosclerotic lesions. Nuclear factor-B (NF-B) is involved in the transcriptional regulation of the proapoptotic protein Fas ligand (FasL). We have analyzed NF-B activation and FasL expression in atherosclerotic plaques and peripheral blood mononuclear cells (PBMCs) of patients with carotid stenosis.

Methods--NF-B activation and FasL and active caspase-3 expression were analyzed in 32 human carotid plaques. NF-B activation and FasL mRNA were tested in PBMCs of patients and healthy volunteers. We analyzed whether the NF-B inhibitor parthenolide regulates FasL expression and cytotoxicity in human T cells.

Results--The inflammatory region of plaques showed an increase in NF-B activation (3393±281 versus 1029±100 positive nuclei per mm², P<0.001) and FasL (16±1.4% versus 13±1.8%, P<0.05) and active caspase-3 (3.3±0.6 versus 1.5±0.3%, P<0.05) expression compared with the fibrous area. Activated NF-B and FasL protein were colocalized in plaque cells. In PBMCs obtained from those patients the day of endarterectomy, NF-B activation and FasL expression were significantly increased compared with healthy controls (1.5±0.1 versus 0.5±0.1 and 2.1±0.1 versus 1.2±0.1 arbitrary units, respectively; P<0.001). There was a significant correlation between NF-B activation and FasL expression. In activated T cells, parthenolide decreased NF-B activation, FasL promoter activity, and mRNA expression. Parthenolide also decreased cytotoxicity of activated Jurkat cells on FasL-sensitive cells.

Conclusions--NF-B activation and FasL overexpression occur in PBMCs and atherosclerotic lesions of patients with carotid stenosis. The NF-B-FasL pathway could be involved in the mechanisms underlying plaque instability in humans.

Key words: apoptosis • atherosclerosis • carotid stenosis

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