垂体腺苷酸环化酶激活肽通过促进肝缺血再灌注损伤中的 Yes 相关蛋白来预防肝细胞损伤。
Pituitary Adenylate Cyclase-activating Polypeptides Prevent Hepatocyte Damage by Promoting Yes-associated Protein in Liver Ischemia-Reperfusion Injury.
机构信息
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
Transplantation. 2019 Aug;103(8):1639-1648. doi: 10.1097/TP.0000000000002742.
BACKGROUND
Hepatic ischemia-reperfusion injury (IRI) is a severe complication in liver transplantation, hepatectomy, and hemorrhagic shock. As neuropeptides transmit the regulatory signal between nervous and immune systems communication, our previous study documented that pituitary adenylate cyclase-activating polypeptides (PACAP) depressed hepatic Toll-like receptor 4 immune response in liver IRI.
METHODS
Here, we focused on how PACAP suppressed hepatocellular damage and enhanced hepatocyte regeneration in a murine model of partial liver warm IRI.
RESULTS
Yes-associated protein (YAP), a cellular modulator of tissue regeneration, was readily induced in wild type (WT) mouse IR-livers. As its induction was failed in PACAP-deficient livers, PACAP supplement enhanced YAP expression in WT mouse and promoted its nuclear translocation and downstream antioxidative/regenerative genes expression both in vivo and in vitro. Further, verteporfin, a YAP transcriptional inhibitor, abolished PACAP-mediated hepatoprotection significantly. Meanwhile, blockade of protein kinase A (PKA)-CRE-binding protein (CREB) signaling recreated liver damage in PACAP-protected liver as well as impeded stimulation on YAP and its downstream gene expressions. Consistently, inhibition of PKA-CREB decreased PACAP-promoted YAP expression in primary hepatocytes culture, and made them vulnerable to H2O2 stress in vitro. In addition, lysophosphatidic acid, another Hippo pathway inhibitor, failed to affect PACAP-mediated hepatoprotection or hepatocellular YAP induction. This implies that PACAP regulated YAP through PKA-CREB pathway at the transcriptional level rather than canonical hippo pathway.
CONCLUSIONS
Our study discovered the neural modulation of PACAP-YAP axis in hepatic cytoprotection and homeostasis in liver IRI. These reveal a novel insight of neuropeptide PACAP in combating liver IRI in clinical patients.
背景
肝缺血再灌注损伤（IRI）是肝移植、肝切除术和失血性休克的严重并发症。神经肽在神经和免疫系统通讯之间传递调节信号，我们之前的研究记录了垂体腺苷酸环化酶激活肽（PACAP）在肝 IRI 中抑制肝 Toll 样受体 4 免疫反应。
方法
在这里，我们专注于 PACAP 如何在小鼠部分肝温 IRI 模型中抑制肝细胞损伤和增强肝细胞再生。
结果
Yes 相关蛋白（YAP），一种组织再生的细胞调节剂，在野生型（WT）鼠 IR 肝中易被诱导。由于其在 PACAP 缺陷型肝脏中诱导失败，PACAP 补充增强了 WT 小鼠的 YAP 表达，并促进了其在体内和体外的核转位和下游抗氧化/再生基因表达。此外，YAP 转录抑制剂 Verteporfin 显著消除了 PACAP 介导的肝保护作用。同时，蛋白激酶 A（PKA）-CRE 结合蛋白（CREB）信号阻断会在 PACAP 保护的肝脏中重建肝损伤，并阻碍 YAP 及其下游基因表达的刺激。一致地，抑制 PKA-CREB 降低了原代肝细胞培养中 PACAP 促进的 YAP 表达，并使它们在体外容易受到 H2O2 应激的影响。此外，另一种 Hippo 通路抑制剂溶血磷脂酸不能影响 PACAP 介导的肝保护或肝细胞 YAP 诱导。这意味着 PACAP 通过 PKA-CREB 通路在转录水平上调节 YAP，而不是经典的 Hippo 通路。
结论
我们的研究发现了 PACAP-YAP 轴在肝 IRI 中肝保护和稳态中的神经调节。这些揭示了神经肽 PACAP 在对抗临床患者肝 IRI 中的新见解。
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