Abstract |
Acetaminophen ( APAP) overdose has become the most common cause of drug-induced acute liver failure. Angiogenesis and redox homeostasis play an important role in liver protection and repair of APAP-induced acute liver injury (AILI). Hypoxia inducible factor-1 (HIF-1) is a transcription factor that plays a crucial role in regulating the expression of genes associated with angiogenesis, redox homeostasis and energy balance. Prolyl hydroxylase 2 (PHD2) predominantly hydroxylates proline residues in HIF-1α to promote its degradation. In our previous study, we reported an intrabody against PHD2 (ER-INP) that enhances angiogenesis by blocking PHD2 activity to increase HIF-1α abundance and activity. The present study was designed to explore the role and possible mechanisms of ER-INP in AILI in mice. Mice were pretreated intravenously with ER-INP before intraperitoneal injection of APAP to induce AILI. The results showed that pretreatment with ER-INP dramatically decreased the high ALT and AST activities and significantly ameliorated the centrilobular necrosis induced by APAP administration. ER-INP expression promoted angiogenesis in vivo by upregulating the mRNA and protein levels of HIF-1α target genes. Meanwhile, ER-INP pretreatment restored redox homeostasis, verified by reinforcement of PRDX4 activity and suppression of GSH depletion. This study demonstrated that ER-INP protects against AILI in part by increasing angiogenesis and maintaining redox homeostasis. These results indicate that ER-INP may provide a potential liver protection strategy against AILI in the future.
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Authors | Liangzhong Zhao, Jialiang Zhao, Ruijuan Gao, Yuan Tian, Ying Zhang, Weiwei Tang, Yu Jiang, Chengjuan Li, Manning Wang, Fang Yang, Guiying Li |
Journal | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
(Biomed Pharmacother)
Vol. 123
Pg. 109783
(Mar 2020)
ISSN: 1950-6007 [Electronic] France |
PMID | 31855737
(Publication Type: Journal Article)
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Copyright | Copyright © 2019 The Author(s). Published by Elsevier Masson SAS.. All rights reserved. |
Chemical References |
- Antibodies
- Hypoxia-Inducible Factor 1, alpha Subunit
- Acetaminophen
- Egln1 protein, mouse
- Hypoxia-Inducible Factor-Proline Dioxygenases
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Topics |
- Acetaminophen
(poisoning)
- Animals
- Antibodies
(immunology)
- Chemical and Drug Induced Liver Injury
(etiology, immunology, prevention & control)
- HEK293 Cells
- Homeostasis
(immunology)
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Hypoxia-Inducible Factor-Proline Dioxygenases
(immunology)
- Male
- Mice
- Mice, Inbred BALB C
- Neovascularization, Physiologic
(immunology)
- Oxidation-Reduction
(drug effects)
- RAW 264.7 Cells
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