Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury

Authors

  • Laura Llacuna,

    1. 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
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    • Laura Llacuna and Montserrat Mari have contributed equally to the work.

  • Montserrat Marí,

    1. 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
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    • Laura Llacuna and Montserrat Mari have contributed equally to the work.

  • Carmen Garcia-Ruiz,

    1. 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
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  • José C. Fernandez-Checa,

    Corresponding author
    1. 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
    • Liver Unit, Hospital Clinic i Provincial c/Villarroel, 170, 08036 Barcelona, Spain
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    • fax: (34) 93-451-5272

    • J. C. Fernandez-Checa and A. Morales share senior authorship.

  • Albert Morales

    Corresponding author
    1. 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
    • Liver Unit, Hospital Clinic i Provincial c/Villarroel, 170, 08036 Barcelona, Spain
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    • J. C. Fernandez-Checa and A. Morales share senior authorship.


  • Potential conflict of interest: Nothing to report.

Abstract

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. (HEPATOLOGY 2006.)

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