Remifentanil preconditioning promotes liver regeneration via upregulation of beta-arrestin 2/ERK/cyclin D1 pathway
Remifentanil preconditioning promotes liver regeneration via upregulation of beta-arrestin 2/ERK/cyclin D1 pathway
复制标题
瑞芬太尼预处理通过上调 β-arrestin 2/ERK/cyclin D1 通路促进肝再生
DOI：
10.1016/j.bbrc.2021.04.008
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发表时间：
2021
影响因子：
3.1
通讯作者：
Yang Li-Qun
中科院分区：
文献类型：
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作者：
Zhu Ling;Zhou Yan-Yu;Zhang Zhi;Yin Su-Qing;Lv Dong-Dong;Wu Yu-Ling;Wang Bao-Shan;Mao Meng-Han;Jiao Ying-Fu;Yu Wei-Feng;Gao Po;Yang Li-Qun
瑞芬太尼是一种有效的短效阿片类止痛药，可通过抗炎作用保护组织免受缺血再灌注损伤。然而，瑞芬太尼在肝切除术后肝再生中的作用尚不清楚。使用70%肝切除小鼠模型，我们发现给予4μg/kg瑞芬太尼的预适应动物通过支持肝细胞增殖而促进肝再生，而不是通过抗炎作用。在40 mM瑞芬太尼促进原代培养小鼠肝细胞增殖的体外实验中，也出现了上述作用。我们进一步证实，瑞芬太尼治疗增加了β-arrestin 2在体内和体外的表达。显示出特异性，瑞芬太尼预适应未能促进肝脏特异性β-arrestin 2基因敲除小鼠的肝再生。虽然瑞芬太尼增加了PHX肝脏中活化的(磷酸化)ERK和细胞周期蛋白D1的表达，但在用瑞芬太尼处理的CKO小鼠和用ERK抑制剂U0126预处理的WT小鼠中，它们的水平没有明显变化。我们的研究结果表明，瑞芬太尼通过上调β-arrestin 2/ERK/细胞周期蛋白D1轴来促进肝再生，这可能有助于改善肝切除术后的再生过程。
Remifentanil is a potent, short-acting opioid analgesic drug that can protect tissues from ischemia and reperfusion injury though anti-inflammatory effects. However, the utility of remifentanil in liver regeneration after hepatectomy is not known. Using a 70% hepatectomy mouse model (PHx), we found that preconditioning animals with 4 μg/kg remifentanil enhanced liver regeneration through supporting hepatocyte proliferation but not through anti-inflammatory effects. These effects were also phenocopied in vitro where 40 mM remifentanil promoted the proliferation of primary mouse hepatocyte cultures. We further identified that remifentanil treatment increased the expression of β-arrestin 2 in vivo and in vitro. Demonstrating specificity, remifentanil preconditioning failed to promote liver regeneration in liver-specific β-arrestin 2 knockout (CKO) mice subjected to PHx. While remifentanil increased the expression of activated (phosphorylated)-ERK and cyclin D1 in PHx livers, their levels were not significantly changed in remifentanil-treated CKO mice nor in WT mice pretreated with the ERK inhibitor U0126. Our findings suggest that remifentanil promotes liver regeneration via upregulation of a β-arrestin 2/ERK/cyclin D1 axis, with implications for improving regeneration process after hepatectomy.