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Published on: August 7, 2012
EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition
Lin-Lin Cai1, Hai-Tao Xu1, Qi-Long Wang1
1Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China.
Abstract:
Prostaglandin E receptor subtype 4 (EP4) is widely distributed in the heart, but its role in hepatic ischemia/reperfusion (I/R), particularly in mitochondrial permeability transition pore (MPTP) modulation, is yet to be elucidated. In the present study, an EP4 agonist (CAY10598) was used in a rat model to evaluate the effects of EP4 activation on liver I/R and the mechanisms underlying this. I/R insult upregulated hepatic EP4 expression during early reperfusion. In addition, subcutaneous CAY10598 injection prior to the onset of reperfusion significantly increased hepatocyte cAMP concentrations and decreased serum ALT and AST levels and necrotic and apoptotic cell percentages, after 6 h of reperfusion. Moreover, CAY10598 protected mitochondrial morphology, markedly inhibited mitochondrial permeability transition pore (MPTP) opening and decreased liver reactive oxygen species levels. This occurred via activation of the ERK1/2‑GSK3β pathway rather than the janus kinase (JAK)2‑signal transducers and activators of transcription (STAT)3 pathway, and resulted in prevention of mitochondria‑associated cell injury. The MPTP opener carboxyatractyloside (CATR) and the ERK1/2 inhibitor PD98059 also partially reversed the protective effects of CAY10598 on the liver and mitochondria. The current findings indicate that EP4 activation induces ERK1/2‑GSK3β signaling and subsequent MPTP inhibition to provide hepatoprotection, and these observations are informative for developing new molecular targets and preventative therapies for I/R in a clinical setting.
Insights
Activating Prostaglandin E receptor subtype 4 (EP4) protects the liver from ischemia/reperfusion (I/R) injury. EP4 activation inhibits mitochondrial permeability transition pore (MPTP) opening via the ERK1/2-GSK3β pathway, reducing liver damage.
Area of Science:
- Hepatology
- Molecular Biology
- Cardiovascular Research
Background:
- Prostaglandin E receptor subtype 4 (EP4) is present in the heart, but its function in liver ischemia/reperfusion (I/R) is unclear.
- The role of EP4 in modulating the mitochondrial permeability transition pore (MPTP) during liver I/R requires further investigation.
Purpose of the Study:
- To investigate the effects of EP4 activation on liver I/R injury in a rat model.
- To elucidate the underlying mechanisms, focusing on MPTP modulation and specific signaling pathways.
Main Methods:
- Utilized a rat model of liver I/R.
- Administered an EP4 agonist (CAY10598) before reperfusion.
- Assessed liver injury markers (ALT, AST), cell death, mitochondrial function, reactive oxygen species (ROS) levels, and key signaling pathways (ERK1/2, GSK3β, JAK2, STAT3).
- Used MPTP opener (CATR) and ERK1/2 inhibitor (PD98059) to confirm pathway involvement.
Main Results:
- EP4 expression increased during early reperfusion following I/R insult.
- CAY10598 treatment reduced serum ALT/AST levels and necrotic/apoptotic cell percentages.
- EP4 activation preserved mitochondrial morphology, inhibited MPTP opening, and decreased ROS production.
- The protective effects were mediated by the ERK1/2-GSK3β pathway, not JAK2-STAT3.
- Inhibition of ERK1/2 or MPTP opening partially reversed CAY10598's protective effects.
Conclusions:
- EP4 activation confers hepatoprotection against I/R injury.
- This protection is achieved through the ERK1/2-GSK3β signaling pathway, leading to MPTP inhibition.
- These findings suggest EP4 as a potential therapeutic target for preventing liver I/R injury.
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