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(Stroke. 2004;35:458.)
© 2004 American Heart Association, Inc.

Original Contributions

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 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.

Correspondence to Professor Jesús Egido, MD, Vascular Research Laboratory, Fundación Jiménez Díaz, Ave Reyes Católicos 2, 28040, Madrid, Spain. 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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