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Sphingosine kinase-2 inhibition improves mitochondrial function and survival after hepatic ischemia-reperfusion
Yanjun Shi1, Hasibur Rehman, Venkat K Ramshesh
1Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
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.
Insights
Sphingosine kinase-2 (SK2) inhibition significantly reduces liver injury and inflammation following ischemia-reperfusion (IR) by preventing mitochondrial dysfunction. This highlights SK2 as a promising therapeutic target for IR injury.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Inflammation Research
Background:
- Ischemia-reperfusion (IR) injury is a significant clinical challenge.
- Mitochondrial permeability transition (MPT) and inflammation are key contributors to liver injury.
- Sphingosine kinase-2 (SK2) role in hepatic IR remains unclear.
Purpose of the Study:
- Investigate the role of SK2 in mitochondrial dysfunction and inflammation post-hepatic IR.
- Evaluate SK2 as a potential therapeutic target for IR injury.
Main Methods:
- Utilized a mouse model of hepatic IR.
- Administered ABC294640, a selective SK2 inhibitor, prior to IR.
- Assessed liver injury, mitochondrial function, MPT, inflammatory markers, and survival.
- Employed cultured hepatocytes to confirm findings.
Main Results:
- IR increased hepatic SK2 and sphingosine-1-phosphate (S1P) levels.
- SK2 inhibition markedly reduced liver injury (54-91%) and mortality (28% to 100%).
- SK2 inhibition prevented MPT, decreased mitochondrial depolarization, and blunted inflammatory responses.
Conclusions:
- SK2 is critically involved in mitochondrial dysfunction, inflammation, and hepatocyte death after hepatic IR.
- Targeting SK2 offers a novel therapeutic strategy for mitigating IR injury.
