EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition.

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.

• Authors: Lin-Lin Cai, Hai-Tao Xu, Qi-Long Wang, Ya-Qing Zhang, Wei Chen, Dong-Yu Zheng, Fang Liu, Hong-Bin Yuan, Yong-Hua Li, Hai-Long Fu
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 45 Issue 6 Pg. 1825-1837 (Jun 2020) ISSN: 1791-244X [Electronic] Greece
• PMID: 32186754 (Publication Type: Journal Article)

Chemical References

• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Reactive Oxygen Species
• Receptors, Prostaglandin E, EP4 Subtype
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat

Topics

• Animals
• Glycogen Synthase Kinase 3 beta (metabolism)
• Liver (metabolism)
• MAP Kinase Signaling System (physiology)
• Male
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Permeability Transition Pore (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Receptors, Prostaglandin E, EP4 Subtype (metabolism)
• Reperfusion Injury (metabolism)
• Signal Transduction (physiology)