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CLINICAL RESEARCH: ATHEROSCLEROSIS

Decreased circulating Fas ligand in patients with familial combined hyperlipidemia or carotid atherosclerosis

Normalization by atorvastatin

Luis Miguel Blanco-Colio, PhD^*, Jose Luis Martín-Ventura, PhD^*, Josep M. Sol, MD, Cristina Díaz, MD, Gonzalo Hernández, MD and Jesús Egido, MD^*,*

^* Vascular Research Laboratory, Fundación Jiménez Díaz, Autonoma University, Madrid, Spain
Research and Development Department, Medical Division, Pfizer, Madrid, Spain

Manuscript received July 3, 2003; revised manuscript received September 23, 2003, accepted October 6, 2003.

^* Reprint requests and correspondence: Prof. Jesus Egido, Vascular Research Laboratory, Fundación Jiménez Díaz, Av. Reyes Católicos 2, 28040 Madrid, Spain.
jegido{at}fjd.es

OBJECTIVES: We sought to study whether patients with familial combined hyperlipidemia (FCH) or carotid atherosclerosis have modified circulating solubilized Fas ligand (sFasL) levels, as well as the potential modifications by atorvastatin. We also examined the effect of atorvastatin on FasL expression and sFasL release in cytokine-stimulated cultured human endothelial cells (ECs).

BACKGROUND: In normal situations, FasL is expressed in most cells, including ECs. Proinflammatory stimuli can downregulate its expression in ECs and facilitate the vascular infiltration of inflammatory cells.

METHODS: We have measured sFasL plasma levels (by ELISA) in 58 patients with FCH, 14 normocholesterolemic patients with carotid atherosclerosis, and 15 healthy volunteers. We analyzed FasL expression (by Western blot analysis) and sFasL release in cultured ECs stimulated with tumor necrosis factor (TNF)-alpha.

RESULTS: Solubilized FasL levels were decreased in hyperlipidemic patients (49 pg/ml), as compared with healthy volunteers (123 pg/ml, p < 0.0001). Patients were randomized to atorvastatin (n = 28) or bezafibrate (n = 30) during 12 months. Atorvastatin treatment increased sFasL concentrations (111 pg/ml, p < 0.0001), reaching normal values. However, treatment with bezafibrate only marginally affected sFasL (85 pg/ml, p < 0.05). Solubilized FasL was also diminished in patients with carotid atherosclerosis (39 pg/ml), and intensive treatment with atorvastatin normalized sFasL levels (90 pg/ml, p = 0.02). Finally, atorvastatin prevented the diminution of FasL expression and sFasL release elicited by TNF-alpha in cultured ECs.

CONCLUSIONS: Patients with FCH or carotid atherosclerosis have decreased circulating sFasL levels, probably indicating endothelial dysfunction, but treatment with atorvastatin restored normal blood levels. These data provide a novel effect of atorvastatin and add support for the well-known anti-inflammatory properties of statins.

Abbreviations and Acronyms   EC = endothelial cell   FCH = familial combined hyperlipidemia   GGPP = geranylgeranyl pyrophosphate   HDL = high-density lipoprotein   HMEC-1 = human microvascular endothelial cell   HMG-CoA = hydroxymethylglutaryl-coenzyme A   LDL = low-density lipoprotein   PBST = phosphate-buffered saline containing 0.1% Tween-20   sFasL = solubilized Fas ligand   TNF = tumor necrosis factor

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