Sphingosine kinase-2 inhibition improves mitochondrial function and survival after hepatic ischemia-reperfusion

Yanjun Shi, Hasibur Rehman, Venkat K. Ramshesh, Justin Schwartz, Qinlong Liu, Yasodha Krishnasamy, Xun Zhang, John J. Lemasters, Charles Smith, Zhi Zhong

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33 Scopus citations

Abstract

Background & Aims: The mitochondrial permeability transition (MPT) and inflammation play important roles in liver injury caused by ischemia-reperfusion (IR). This study investigated the roles of sphingosine kinase-2 (SK2) in mitochondrial dysfunction and inflammation after hepatic IR. Methods: Mice were gavaged with vehicle or ABC294640 (50 mg/kg), a selective inhibitor of SK2, 1 h before surgery and subjected to 1 h-warm ischemia to ∼70% of the liver followed by reperfusion. Results: Following IR, hepatic SK2 mRNA and sphingosine-1-phosphate (S1P) levels increased ∼25- and 3-fold, respectively. SK2 inhibition blunted S1P production and liver injury by 54-91%, and increased mouse survival from 28% to 100%. At 2 h after reperfusion, mitochondrial depolarization was observed in 74% of viable hepatocytes, and mitochondrial voids excluding calcein disappeared, indicating MPT onset in vivo. SK2 inhibition decreased mitochondrial depolarization and prevented MPT onset. Inducible nitric oxide synthase, phosphorylated NFκB-p65, TNFα mRNA, and neutrophil infiltration, all increased markedly after hepatic IR, and these increases were blunted by SK2 inhibition. In cultured hepatocytes, anoxia/re-oxygenation resulted in increases of SK2 mRNA, S1P levels, and cell death. SK2 siRNA and ABC294640 each substantially decreased S1P production and cell death in cultured hepatocytes. Conclusions: SK2 plays an important role in mitochondrial dysfunction, inflammation responses, hepatocyte death, and survival after hepatic IR and represents a new target for the treatment of IR injury.

Original languageEnglish (US)
Pages (from-to)137-145
Number of pages9
JournalJournal of Hepatology
Volume56
Issue number1
DOIs
StatePublished - Jan 1 2012

All Science Journal Classification (ASJC) codes

  • Hepatology

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    Shi, Y., Rehman, H., Ramshesh, V. K., Schwartz, J., Liu, Q., Krishnasamy, Y., Zhang, X., Lemasters, J. J., Smith, C., & Zhong, Z. (2012). Sphingosine kinase-2 inhibition improves mitochondrial function and survival after hepatic ischemia-reperfusion. Journal of Hepatology, 56(1), 137-145. https://doi.org/10.1016/j.jhep.2011.05.025