Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury.
The molecular mechanisms of hepatic ischemia/reperfusion (I/R) damage are incompletely understood. We investigated the role of ceramide in a murine model of warm hepatic I/R injury. This sphingolipid induces cell death and participates in tumor necrosis factor (TNF) signaling. Hepatic ceramide levels transiently increased after the reperfusion phase of the ischemic liver in mice, because of an early activation of acidic sphingomyelinase (ASMase) followed by acid ceramidase stimulation. In vivo administration of an ASMase inhibitor, imipramine, or ASMase knockdown by siRNA decreased ceramide generation during I/R, and attenuated serum ALT levels, hepatocellular necrosis, cytochrome c release, and caspase-3 activation. ASMase-induced ceramide generation activated JNK resulting in BimL phosphorylation and translocation to mitochondria, as the inhibition of ASMase by imipramine prevented these events. In contrast, blockade of ceramide catabolism by N-oleyolethanolamine (NOE), a ceramidase inhibitor, enhanced ceramide levels and potentiated I/R injury compared with vehicle-treated mice. Pentoxifylline treatment prevented TNF upregulation and ASMase activation. Furthermore, 9 of 11 mice treated with imipramine survived 7 days after total liver ischemia, compared with 4 of 12 vehicle-treated mice, whereas 8 of 8 NOE-treated mice died within 2 days of total liver ischemia. In conclusion, ceramide generated from ASMase plays a key role in I/R-induced liver damage, and its modulation may be of therapeutic relevance.
Llacuna
Laura
L
Liver Unit, Hospital Clínic, Instituto Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), and the Department of Experimental Pathology, Instituto Investigaciones Biomédicas Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
Marí
Montserrat
M
Garcia-Ruiz
Carmen
C
Fernandez-Checa
José C
JC
Morales
Albert
A
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D015536:Down-Regulation; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D005500:Follow-Up Studies; D002517:Galactosylgalactosylglucosylceramidase / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009829:Oleic Acids; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009829:Oleic Acids; D012333:RNA, Messenger; C033595:N-oleoylethanolamine; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D002517:Galactosylgalactosylglucosylceramidase