Decreased circulating Fas ligand in patients with familial combined hyperlipidemia or carotid atherosclerosis: normalization by atorvastatin.
OBJECTIVE
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.
Blanco-Colio
Luis Miguel
LM
Vascular Research Laboratory, Fundación Jiménez Díaz, Autonoma University, Madrid, Spain.
Martín-Ventura
Jose Luis
JL
Sol
Josep M
JM
Díaz
Cristina
C
Hernández
Gonzalo
G
Egido
Jesús
J
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000069059:Atorvastatin; D001629:Bezafibrate / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000378:metabolism*; D017536:Carotid Artery, Common / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D004311:Double-Blind Method; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006950:Hyperlipidemia, Familial Combined / Q000188:drug therapy / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D008875:Middle Aged; D011758:Pyrroles / Q000627:therapeutic use; D013729:Terpenes / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D000970:Antineoplastic Agents; D015415:Biomarkers; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008562:Membrane Glycoproteins; D011758:Pyrroles; D013729:Terpenes; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin; D008798:Mevalonic Acid; D001629:Bezafibrate