NF- B Activation and Fas Ligand Overexpression in Blood and Plaques of Patients With Carotid Atherosclerosis: Potential Implication in Plaque Instability (original) (raw)

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 (3393Ϯ281 versus 1029Ϯ100 positive nuclei per mm 2 , PϽ0.001) and FasL (16Ϯ1.4% versus 13Ϯ1.8%, PϽ0.05) and active caspase-3 (3.3Ϯ0.6 versus 1.5Ϯ0.3%, PϽ0.05) 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 (1.5Ϯ0.1 versus 0.5Ϯ0.1 and 2.1Ϯ0.1 versus 1.2Ϯ0.1 arbitrary units, respectively; PϽ0.001). 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. (Stroke. 2004;35:458-463.