Effect of simvastatin on endothelial cell apoptosis mediated by Fas and TNF-alpha.
Although there is evidence suggesting that statins may exert an endothelial protecting effect, recent in vitro data have shown that these compounds may induce endothelial cells (EC) apoptosis. We previously reported that the Fas-death receptor may induce apoptosis of the liver sinusoid endothelial cells (LSEC), and that TNF-alpha increases the susceptibility of these cells to suffer Fas-mediated apoptosis. Based on this evidence, in this study, we investigated the effect of simvastatin on Fas-mediated LSEC apoptosis. Simvastatin induced a significant reduction in LSEC viability, in a dose dependent manner, under serum-containing or serum-free conditions. This effect was prevented by mevalonate and GGPP, indicating the role of hydroxy-3-methylglutaryl-CoA reductase. The simvastatin effect on LSEC death was not associated with increased activation of caspase-3. We found that simvastatin increased the susceptibility of LSEC death mediated by Fas. Further, simvastatin increased LSEC-apoptosis induced by Fas and TNF-alpha. Mevalonate and GGPP partially prevented simvastatin-induced sensitization to LSEC death mediated by Jo2 and TNF-alpha, but not Jo2 alone. Simvastatin did not induce up-regulation of the Fas on the LSEC. Our results provide evidence of simvastatin in modulating Fas-mediated apoptosis in endothelial cells. These results may have clinical implications in those clinical conditions associated with high levels of FasL and TNF-alpha.
Acquavella
Nicolas
N
Laboratorio de Patología Celular y Molecular, Centro de Medicina Experimental, Instituto Venezolano de Investigaciones Científicas (IVIC), Apartado 21827, Caracas 1020-A, Venezuela.
Quiroga
Maria F
MF
Wittig
Olga
O
Cardier
Jose E
JE
D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003513:Cycloheximide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology*; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D000974:Antibodies, Antinuclear; D000924:Anticholesteremic Agents; D053222:Fas Ligand Protein; D011106:Polyisoprenyl Phosphates; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D003513:Cycloheximide; D019821:Simvastatin; D053148:Caspase 3; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid