The novel prolyl hydroxylase-2 inhibitor caffeic acid upregulates hypoxia inducible factor and protects against hypoxia

Guo, Zhouliang, Yang, Yang, Li, Lu, Zhao, Qing, Li, Yuyin, Liu, Zhenxing, Hao, Limin, Guo, Baoqiang ORCID: https://orcid.org/0000-0002-5469-4621 and Diao, Aipo (2022) The novel prolyl hydroxylase-2 inhibitor caffeic acid upregulates hypoxia inducible factor and protects against hypoxia. European Journal of Clinical Pharmacology, 934. 175307. ISSN 0031-6970

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Official URL: https://doi.org/10.1016/j.ejphar.2022.175307

Abstract

Background & aims: Hypoxia inducible factor (HIF) is a hypoxia-associated transcription factor that has a protective role against hypoxia-induced damage. Prolyl hydroxylase-2 (PHD2) is a dioxygenase enzyme that specifically hydroxylates HIF targeting it for degradation, therefore, inhibition of the PHD2 enzyme activity acts to upregulate HIF function. This study was to identify novel PHD2 inhibitors. Methods: An established fluorescence-based PHD2 activity assay was used for inhibitors screening. Western blot and quantitative real-time PCR was used to detect the protein and mRNA levels respectively. Further animal experiment was carried out. Results: Caffeic acid was screened and identified as a novel PHD2 inhibitor. Caffeic acid treated PC12 and SH-SY5Y neuronal cell lines stabilized endogenous HIF-1α protein levels and consequently increased mRNA levels of its downstream regulated genes VEGF and EPO. Caffeic acid treatment reduced hypoxia-induced cell apoptosis and promoted HIF/BNIP3-mediated mitophagy. Moreover, animal studies indicated that caffeic acid increased the level of HIF-1α protein and mRNA levels of VEGF and EPO in the brain of mice exposed to hypoxia. Conventional brain injury markers including malondialdehyde, lactic acid and lactate dehydrogenase in the caffeic acid treated mice were shown to be reduced to the levels of the control group. Conclusions: This study suggests that caffeic acid inhibits PHD2 enzyme activity which then activates the hypoxia-associated transcription factor HIF leading to a neuroprotective effect against hypoxia.

Item Type:	Article (Article)
Peer-reviewed:	Yes
Date Deposited:	14 Nov 2023 15:18
Publisher:	Elsevier
Additional Information:	© 2022. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
Divisions:	Faculties > Science and Engineering
Subject terms:	Animals, Humans, Mice, Neuroblastoma, Malondialdehyde, Lactic Acid, Lactate Dehydrogenases, Procollagen-Proline Dioxygenase, Vascular Endothelial Growth Factor A, Transcription Factors, RNA, Messenger, Neuroprotective Agents, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Prolyl-Hydroxylase Inhibitors, Hypoxia, Caffeic acid, HIF, Hypoxia, Mitophagy, PHD2, Humans, Mice, Animals, Hypoxia-Inducible Factor-Proline Dioxygenases, Prolyl-Hydroxylase Inhibitors, Vascular Endothelial Growth Factor A, Neuroprotective Agents, Neuroblastoma, Procollagen-Proline Dioxygenase, Hypoxia, RNA, Messenger, Lactic Acid, Malondialdehyde, Lactate Dehydrogenases, Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit, 1115 Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
Data Access Statement:	Data will be made available on request.
URI:	https://e-space.mmu.ac.uk/id/eprint/632940
DOI:	https://doi.org/10.1016/j.ejphar.2022.175307
ISSN	0031-6970
e-ISSN	1879-0712

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