PMID- 37507007
OWN - NLM
STAT- MEDLINE
DCOM- 20231106
LR  - 20240304
IS  - 1878-1810 (Electronic)
IS  - 1878-1810 (Linking)
VI  - 262
DP  - 2023 Dec
TI  - Dual-regulation by Cx32 in hepatocyte to trigger and worsen liver graft injury.
PG  - 44-59
LID - S1931-5244(23)00124-X [pii]
LID - 10.1016/j.trsl.2023.07.008 [doi]
AB  - Liver transplantation is the ultimate treatment option for end-stage liver 
      failure. However, liver graft injury remains a challenge. This study aimed to 
      investigate the role of connexin32 (Cx32) in liver graft injury and elucidate its 
      mechanism of action. Through detecting liver graft samples from 6 patients, we 
      observed that changes in the Cx32 level coincided with liver graft injury. 
      Therefore, we established autologous orthotopic liver transplantation (AOLT) 
      models using Cx32-knockout and wild-type mice and hypoxia/reoxygenation (H/R) and 
      lipopolysaccharide (LPS) pretreatment models using alpha mouse liver 12 (AML12) 
      cells, to explore Cx32 mechanisms in liver graft injury. Following in vivo and in 
      vitro Cx32 knockout, oxidative stress and inflammatory response were inhibited 
      through the regulation of PKC-alpha/NF-kappaB/NLRP3 and Nrf2/NOX4/ROS signaling pathways, 
      thereby reducing Bak/Bax-related apoptosis and ameliorating liver graft injury. 
      When the Cx32-based gap junction (GJ) was blocked with 2-aminoethoxydiphenyl 
      borate (2-APB), ROS transfer was attenuated between neighboring cells, 
      exacerbated oxidative stress and inflammatory response were prevented, and 
      aggravation of liver graft injury was mitigated. These results highlight the dual 
      regulation mechanism of Cx32 in liver graft injury. Through interaction with 
      PKC-alpha, Cx32 regulated the NF-kappaB/NLRP3 and Nrf2/NOX4/ROS signaling pathways, thus 
      directly triggering oxidative stress and inflammatory response. Simultaneously, 
      mass-produced ROS were transferred to neighboring cells through Cx32 channels, 
      for which oxidative stress and the inflammatory response were aggravated 
      indirectly. Finally, Bak/Bax-related apoptosis was activated, thereby worsening 
      liver graft injury. Our findings propose Cx32 as a dual mechanistic factor for 
      oxidative stress and inflammatory signaling pathways in regulating cell apoptosis 
      on liver graft injury, which suggests a promising therapeutic targets for liver 
      graft injury.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Huang, Fei
AU  - Huang F
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China.
FAU - Deng, Zhizhao
AU  - Deng Z
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China.
FAU - Zhang, Qian
AU  - Zhang Q
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China.
FAU - Zhang, Zheng
AU  - Zhang Z
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China.
FAU - Li, Xianlong
AU  - Li X
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China.
FAU - Zeng, Weiqi
AU  - Zeng W
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China.
FAU - Wang, Yanling
AU  - Wang Y
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China. Electronic address: 
      wyl-5120@163.com.
FAU - Hei, Ziqing
AU  - Hei Z
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China. Electronic address: 
      heiziqing@sina.com.
FAU - Yuan, Dongdong
AU  - Yuan D
AD  - Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, Guangdong, P. R. China. Electronic address: 
      yuandongdong123@126.com.
LA  - eng
PT  - Journal Article
DEP - 20230726
PL  - United States
TA  - Transl Res
JT  - Translational research : the journal of laboratory and clinical medicine
JID - 101280339
RN  - 0 (NF-kappa B)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (bcl-2-Associated X Protein)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - *Liver Transplantation
MH  - NF-kappa B/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - NF-E2-Related Factor 2
MH  - bcl-2-Associated X Protein/metabolism
MH  - Liver/metabolism
MH  - Hepatocytes
OTO - NOTNLM
OT  - Apoptosis
OT  - Connexin32
OT  - Gap junction
OT  - Inflammatory response
OT  - Liver graft injury
OT  - Oxidative stress
EDAT- 2023/07/29 06:41
MHDA- 2023/11/06 06:42
CRDT- 2023/07/28 19:17
PHST- 2023/03/28 00:00 [received]
PHST- 2023/06/28 00:00 [revised]
PHST- 2023/07/23 00:00 [accepted]
PHST- 2023/11/06 06:42 [medline]
PHST- 2023/07/29 06:41 [pubmed]
PHST- 2023/07/28 19:17 [entrez]
AID - S1931-5244(23)00124-X [pii]
AID - 10.1016/j.trsl.2023.07.008 [doi]
PST - ppublish
SO  - Transl Res. 2023 Dec;262:44-59. doi: 10.1016/j.trsl.2023.07.008. Epub 2023 Jul 
      26.