Open Access

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

  • 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
  • View Affiliations

  • Published online on: March 17, 2020     https://doi.org/10.3892/ijmm.2020.4544
  • Pages: 1825-1837
  • Copyright: © Cai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


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.
View Figures
View References

Related Articles

Journal Cover

June-2020
Volume 45 Issue 6

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Cai LL, Xu HT, Wang QL, Zhang YQ, Chen W, Zheng DY, Liu F, Yuan HB, Li YH, Fu HL, Fu HL, et al: EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition. Int J Mol Med 45: 1825-1837, 2020.
APA
Cai, L., Xu, H., Wang, Q., Zhang, Y., Chen, W., Zheng, D. ... Fu, H. (2020). EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition. International Journal of Molecular Medicine, 45, 1825-1837. https://doi.org/10.3892/ijmm.2020.4544
MLA
Cai, L., Xu, H., Wang, Q., Zhang, Y., Chen, W., Zheng, D., Liu, F., Yuan, H., Li, Y., Fu, H."EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition". International Journal of Molecular Medicine 45.6 (2020): 1825-1837.
Chicago
Cai, L., Xu, H., Wang, Q., Zhang, Y., Chen, W., Zheng, D., Liu, F., Yuan, H., Li, Y., Fu, H."EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition". International Journal of Molecular Medicine 45, no. 6 (2020): 1825-1837. https://doi.org/10.3892/ijmm.2020.4544