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

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.

• Authors: Yanjun Shi, Hasibur Rehman, Venkat K Ramshesh, Justin Schwartz, Qinlong Liu, Yasodha Krishnasamy, Xun Zhang, John J Lemasters, Charles D Smith, Zhi Zhong
• Journal: Journal of hepatology (J Hepatol) Vol. 56 Issue 1 Pg. 137-45 (Jan 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 21756852 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Lysophospholipids
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Pyridines
• RNA, Messenger
• RNA, Small Interfering
• sphingosine 1-phosphate
• 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Sphingosine
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Cell Death (drug effects)
• Enzyme Inhibitors (pharmacology)
• Gene Knockdown Techniques
• Hepatocytes (drug effects, metabolism)
• In Vitro Techniques
• Inflammation (enzymology, genetics)
• Liver (drug effects, enzymology, injuries)
• Lysophospholipids (metabolism, pharmacology)
• Male
• Mice
• Mitochondria, Liver (drug effects, enzymology)
• Mitochondrial Membrane Transport Proteins (drug effects, metabolism)
• Mitochondrial Permeability Transition Pore
• Nitric Oxide Synthase Type II (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors)
• Pyridines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Reperfusion Injury (drug therapy, enzymology, genetics)
• Sphingosine (analogs & derivatives, metabolism, pharmacology)