线粒体通透性转换孔
MPTP公司
再灌注损伤
药理学
线粒体
肝保护
信号转导
活性氧
化学
生物
细胞生物学
细胞凋亡
内分泌学
缺血
内科学
医学
程序性细胞死亡
生物化学
谷胱甘肽
多巴胺
酶
多巴胺能
作者
Linlin Cai,Haitao Xu,Qi‐Long Wang,Ya‐Qing Zhang,Wei Chen,Dongyu Zheng,Fang Liu,Hongbin Yuan,Yonghua Li,Hailong Fu
标识
DOI:10.3892/ijmm.2020.4544
摘要
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.
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