Farnesyltransferase inhibitor improved survival following endotoxin challenge in mice.
Endotoxemia plays an important role in the pathogenesis of sepsis and is accompanied by dysregulated apoptosis of immune and non-immune cells. Treatment with statins reduces mortality in rodent models of sepsis and endotoxemia. Inhibition of protein isoprenylation, including farnesylation, has been proposed as a mechanism to mediate the lipid-lowering-independent effects of statins. Nonetheless, the effects of the inhibition of isoprenylation have not yet been studied. To investigate the role of farnesylation, we evaluated the effects of farnesyltransferase inhibitor and statin on survival following lipopolysaccharide (LPS) challenge in mice. Both simvastatin (2mg/kg BW) and FTI-277 (20mg/kg BW) treatment improved survival by twofold after LPS injection, as compared with vehicle alone (p<0.01). LPS-induced cleavage (activation) of caspase-3, an indicator of apoptotic change, and increased protein expression of proapoptotic molecules, Bax and Bim, and activation of c-Jun NH(2)-terminal kinase (JNK/SAPK) in the liver and spleen were attenuated by both simvastatin and FTI-277. These results demonstrate that farnesyltransferase inhibitor as well as statin significantly reduced LPS-induced mortality in mice. Our findings also suggest that inhibition of protein farnesylation may contribute to the lipid-lowering-independent protective effects of statins in endotoxemia, and that protein farnesylation may play a role in LPS-induced stress response, including JNK/SAPK activation, and apoptotic change. Our data argue that farnesyltransferase may be a potential molecular target for treating patients with endotoxemia.
Shinozaki
Shohei
S
Shriners Hospitals for Children, Boston, MA 02114, USA.
Inoue
Yoko
Y
Yang
Wen
W
Fukaya
Makiko
M
Carter
Edward A
EA
Yu
Yong-Ming
YM
Ming-Yu
Young
Y
Fischman
Alan
A
Tompkins
Ronald
R
Kaneki
Masao
M
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D019821:Simvastatin / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D004791:Enzyme Inhibitors; C096856:FTI 277; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D008715:Methionine; D019821:Simvastatin; D051231:Farnesyltranstransferase; D048670:MAP Kinase Kinase 4