Protective effects of connexin43 signaling in acetaminophen-induced liver injury

Michaël Maes, Mitchell R. Mcgill, Tereza Cristina da Silva, Margitta Lebofsky, Isabel Veloso Alves Pereira, Joost Willebrords, Sara Crespo Yanguas, Anwar Farhood, Maria Lucia Zaidan Dagli, Hartmut Jaeschke, Bruno Cogliati, Mathieu Vinken

Onderzoeksoutput: Meeting abstract (Journal)

Samenvatting

Background and aims: Being goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for druginduced liver insults. In the present study, the role and functional relevance of connexin32 and connexin43, the building stones of liver gap junctions, were investigated in acetaminopheninduced hepatotoxicity. Methods: C57BL/6 mice were overdosed with acetaminophen followed by analysis of the expression and localization of connexins as well as monitoring of hepatic gap junction functionality. Furthermore, acetaminophen-induced liver injury was compared between mice genetically deficient in either connexin32 or connexin43 and wild type animals. Evaluation of the toxicological response was based on a set of clinically relevant parameters, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase, cytokines, reduced and oxidized glutathione, and analysis of proliferating cell nuclear antigen expression. Results: It was found that gap junction communication deteriorates upon acetaminophen intoxication in wild type mice, which was associated with a switch in mRNA and protein production from connexin32 to connexin43. Furthermore, connexin43-deficient animals showed increased liver cell death, inflammation and oxidative stress in comparison with wild type counterparts, whereas the opposite seems to hold true for mice lacking connexin32. Conclusion: These results suggest that hepatic connexin43-based signaling protects against acetaminophen-induced liver toxicity.
Originele taal-2English
Artikelnummer586
Pagina's (van-tot)500A-500A
TijdschriftHepatology
Volume62
Nummer van het tijdschriftSI
StatusPublished - 1 okt 2015
EvenementThe Liver Meeting 2015 from the American Association for the Study of Liver Diseases - San Francisco, United States
Duur: 13 nov 201517 nov 2015

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