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Intrabody against prolyl hydroxylase 2 ameliorates acetaminophen-induced acute liver injury in mice via concomitant promotion of angiogenesis and redox homeostasis.

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.
AuthorsLiangzhong Zhao, Jialiang Zhao, Ruijuan Gao, Yuan Tian, Ying Zhang, Weiwei Tang, Yu Jiang, Chengjuan Li, Manning Wang, Fang Yang, Guiying Li
JournalBiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 123 Pg. 109783 (Mar 2020) ISSN: 1950-6007 [Electronic] France
PMID31855737 (Publication Type: Journal Article)
CopyrightCopyright © 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
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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