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Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

Michaël Maes, Sara Crespo Yanguas, Joost Willebrords, James L Weemhoff, Tereza Cristina da Silva, Elke Decrock UGent, Margitta Lebofsky, Isabel Veloso Alves Pereira, Luc Leybaert UGent, Anwar Farhood, et al. (2017) TOXICOLOGY LETTERS. 278. p.30-37
abstract
Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficacy of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5h. Sampling was performed 3, 6, 24 and 48h following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
Acetaminophen, Connexin, Gap junction, Hemichannel, Hepatotoxicity, Inflammation, GAP JUNCTIONAL COMMUNICATION, CELL-DEATH, OXIDANT STRESS, INTERCELLULAR COMMUNICATION, GLYCYRRHETINIC ACID, PROTEIN ADDUCTS, HEPATOTOXICITY, FAILURE, ASTROCYTES, CHANNELS
journal title
TOXICOLOGY LETTERS
Toxicol. Lett.
volume
278
pages
30 - 37
Web of Science type
Article
Web of Science id
000407566100004
ISSN
0378-4274
DOI
10.1016/j.toxlet.2017.07.007
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8540461
handle
http://hdl.handle.net/1854/LU-8540461
date created
2017-12-06 10:33:37
date last changed
2018-01-09 10:47:09
@article{8540461,
  abstract     = {Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficacy of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5h. Sampling was performed 3, 6, 24 and 48h following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.},
  author       = {Maes, Micha{\"e}l and Crespo Yanguas, Sara and Willebrords, Joost and Weemhoff, James L and da Silva, Tereza Cristina and Decrock, Elke and Lebofsky, Margitta and Alves Pereira, Isabel Veloso and Leybaert, Luc and Farhood, Anwar and Jaeschke, Hartmut and Cogliati, Bruno and Vinken, Mathieu},
  issn         = {0378-4274},
  journal      = {TOXICOLOGY LETTERS},
  keyword      = {Acetaminophen,Connexin,Gap junction,Hemichannel,Hepatotoxicity,Inflammation,GAP JUNCTIONAL COMMUNICATION,CELL-DEATH,OXIDANT STRESS,INTERCELLULAR COMMUNICATION,GLYCYRRHETINIC ACID,PROTEIN ADDUCTS,HEPATOTOXICITY,FAILURE,ASTROCYTES,CHANNELS},
  language     = {eng},
  pages        = {30--37},
  title        = {Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice},
  url          = {http://dx.doi.org/10.1016/j.toxlet.2017.07.007},
  volume       = {278},
  year         = {2017},
}

Chicago
Maes, Michaël, Sara Crespo Yanguas, Joost Willebrords, James L Weemhoff, Tereza Cristina da Silva, Elke Decrock, Margitta Lebofsky, et al. 2017. “Connexin Hemichannel Inhibition Reduces Acetaminophen-induced Liver Injury in Mice.” Toxicology Letters 278: 30–37.
APA
Maes, Michaël, Crespo Yanguas, S., Willebrords, J., Weemhoff, J. L., da Silva, T. C., Decrock, E., Lebofsky, M., et al. (2017). Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice. TOXICOLOGY LETTERS, 278, 30–37.
Vancouver
1.
Maes M, Crespo Yanguas S, Willebrords J, Weemhoff JL, da Silva TC, Decrock E, et al. Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice. TOXICOLOGY LETTERS. 2017;278:30–7.
MLA
Maes, Michaël, Sara Crespo Yanguas, Joost Willebrords, et al. “Connexin Hemichannel Inhibition Reduces Acetaminophen-induced Liver Injury in Mice.” TOXICOLOGY LETTERS 278 (2017): 30–37. Print.