TY - JOUR
T1 - Pituitary adenylate cyclase-Activating polypeptides prevent hepatocyte damage by promoting yes-Associated protein in liver ischemia-reperfusion injury
AU - Liu, Yuan
AU - Lu, Tianfei
AU - Zhang, Cheng
AU - Xue, Zhengze
AU - Xu, Jin
AU - Busuttil, Ronald W.
AU - Xia, Qiang
AU - Xu, Ning
AU - Kupiec-Weglinski, Jerzy W.
AU - Ji, Haofeng
N1 - Funding Information:
This work was supported by grants from NIH R21 AI122155 and AI138165 (H.J.), NIH PO1 AI120944, RO1 DK107533, DK102110, and DK062357 (J.W.K.W.), and The Dumont Research Foundation.
Publisher Copyright:
Copyright © 2019 Wolters Kluwer Health, Inc.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
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U2 - 10.1097/TP.0000000000002742
DO - 10.1097/TP.0000000000002742
M3 - Article
C2 - 31348437
AN - SCOPUS:85070615838
SN - 0041-1337
VL - 103
SP - 1639
EP - 1648
JO - Transplantation
JF - Transplantation
IS - 8
ER -