Intrabody against prolyl hydroxylase 2 ameliorates acetaminophen-induced acute liver injury in mice via concomitant promotion of angiogenesis and redox homeostasis.
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.
['Zhao|Liangzhong|L|', 'Zhao|Jialiang|J|', 'Gao|Ruijuan|R|', 'Tian|Yuan|Y|', 'Zhang|Ying|Y|', 'Tang|Weiwei|W|', 'Jiang|Yu|Y|', 'Li|Chengjuan|C|', 'Wang|Manning|M|', 'Yang|Fang|F|', 'Li|Guiying|G|']
D000082:Acetaminophen D000818:Animals D000906:Antibodies D056486:Chemical and Drug Induced Liver Injury D057809:HEK293 Cells D006706:Homeostasis D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D064799:Hypoxia-Inducible Factor-Proline Dioxygenases D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D018919:Neovascularization, Physiologic D010084:Oxidation-Reduction D000067996:RAW 264.7 Cells
Intrabody Prolyl hydroxylase 2 Acetaminophen-induced acute liver injury Angiogenesis Redox homeostasis Hypoxia inducible factor-1