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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

View larger version (16K): [in a new window]   Figure 1 Effect of hyperlipidemia on solubilized Fas ligand (sFasL) levels. Representation of sFasL concentrations in healthy volunteers and hyperlipidemic patients. Data are expressed as median values.

View larger version (20K): [in a new window]   Figure 2 Effect of atorvastatin or bezafibrate treatment on circulating solubilized Fas ligand (sFasL) levels in patients with hyperlipidemia. Atorvastatin treatment normalized sFasL levels in hyperlipidemic patients at six (striped bars) and 12 months (solid bars). Open bars = baseline. Data are expressed as median values. *p < 0.0001 and p < 0.0005 compared with healthy subjects.

View larger version (15K): [in a new window]   Figure 3 Changes in solubilized Fas ligand (sFasL) after treatment with atorvastatin (open bars) and bezafibrate (solid bars). Data are expressed as the change in median value with respect to baseline.

View larger version (12K): [in a new window]   Figure 4 Effect of atorvastatin on circulating solubilized Fas ligand (sFasL) in patients with carotid atherosclerosis. Atorvastatin treatment (open bars) increased sFasL levels in patients with carotid atherosclerosis at four to six weeks. Solid bars = no treatment. Data are expressed as median values.

View larger version (24K): [in a new window]   Figure 5 Effect of atorvastatin on Fas ligand (FasL) expression and solubilized Fas ligand (sFasL) released by human cultured endothelial cells (ECs). Endothelial cells were preincubated for 2 h with atorvastatin (Atv). (A) Western blot showing the effect of atorvastatin on FasL expression in ECs. (B) TNF-alpha decreased sFasL release by ECs at 6 h. Treatment with atorvastatin normalized circulating sFasL levels in a dose-dependent manner. *p < 0.05 vs. baseline; p < 0.05 vs. 25 ng/ml tumor necrosis factor (TNF)-alpha. (C) Treatment with atorvastatin (10 µmol/l) prevented the diminution of sFasL induced by TNF-alpha (*p < 0.05 vs. 25 ng/ml TNF-alpha).

View larger version (24K): [in a new window]   Figure 6 Effect of mevalonate (MVA) or isoprenoids on Fas ligand (FasL) expression and solubilized Fas ligand (sFasL) released by human cultured endothelial cells (ECs). Endothelial cells were preincubated for 2 h with atorvastatin (Atv), mevalonate, or isoprenoids and then 6 h with tumor necrosis factor (TNF)-alpha (25 ng/ml). (A) Western blot showing the effect of mevalonate, farnesyl pyrophosphate (FPP), or geranylgeranyl pyrophosphate (GGPP) on FasL expression in ECs. (B) Mevalonate and GGPP decreased sFasL release by ECs in the presence of atorvastatin (*p < 0.05 vs. atorvastatin).