Pituitary Adenylate Cyclase-activating Polypeptides Prevent Hepatocyte Damage by Promoting Yes-associated Protein in Liver Ischemia-Reperfusion Injury.

Autor:	Liu Y; 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., Lu T; 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., Zhang C; 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 Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China., Xue Z; 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 Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China., Xu J; 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 Pancreatic Surgery, Shengjing Hospital, China Medical University, Shenyang, China., Busuttil RW; 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., Xia Q; Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Xu N; Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Kupiec-Weglinski JW; 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., Ji H; 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.
Jazyk:	angličtina
Zdroj:	Transplantation [Transplantation] 2019 Aug; Vol. 103 (8), pp. 1639-1648.
DOI:	10.1097/TP.0000000000002742
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu