University of Oulu

Dengler, F.; Sova, S.; Salo, A.M.; Mäki, J.M.; Koivunen, P.; Myllyharju, J. Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium. Int. J. Mol. Sci. 2021, 22, 4038.

Expression and roles of individual HIF prolyl 4-hydroxylase isoenzymes in the regulation of the hypoxia response pathway along the murine gastrointestinal epithelium

Saved in:
Author: Dengler, Franziska1,2,3; Sova, Sofia2; Salo, Antti M.2;
Organizations: 1Unit of Physiology, Pathophysiology and Experimental Endocrinology, University of Veterinary Medicine, 1210 Vienna, Austria
2Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
3Institute of Veterinary Physiology, University of Leipzig, 04103 Leipzig, Germany
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.4 MB)
Persistent link:
Language: English
Published: Multidisciplinary Digital Publishing Institute, 2021
Publish Date: 2021-07-07


The HIF prolyl 4-hydroxylases (HIF-P4H) control hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. The gastrointestinal epithelium subsists in “physiological hypoxia” and should therefore have an especially well-designed control over this adaptation. Thus, we assessed the absolute mRNA expression levels of the HIF pathway components, Hif1a, HIF2a, Hif-p4h-1, 2 and 3 and factor inhibiting HIF (Fih1) in murine jejunum, caecum and colon epithelium using droplet digital PCR. We found a higher expression of all these genes towards the distal end of the gastrointestinal tract. We detected mRNA for Hif-p4h-1, 2 and 3 in all parts of the gastrointestinal tract. Hif-p4h-2 had significantly higher expression levels compared to Hif-p4h-1 and 3 in colon and caecum epithelium. To test the roles each HIF-P4H isoform plays in the gut epithelium, we measured the gene expression of classical HIF target genes in Hif-p4h-1−/−, Hif-p4h-2 hypomorph and Hif-p4h-3−/− mice. Only Hif-p4h-2 hypomorphism led to an upregulation of HIF target genes, confirming a predominant role of HIF-P4H-2. However, the abundance of Hif-p4h-1 and 3 expression in the gastrointestinal epithelium implies that these isoforms may have specific functions as well. Thus, the development of selective inhibitors might be useful for diverging therapeutic needs.

see all

Series: International journal of molecular sciences
ISSN: 1661-6596
ISSN-E: 1422-0067
ISSN-L: 1661-6596
Volume: 22
Issue: 8
Article number: 4038
DOI: 10.3390/ijms22084038
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This study was supported by an EMBO short-term fellowship and a FEBS fellowship (FD), Academy of Finland Grants 296498 (JM) and 308009 (PK), Sigrid Jusélius Foundation Grants (JM, PK) and Jane and Aatos Erkko Foundation Grant (JM, PK).
Academy of Finland Grant Number: 296498
Detailed Information: 296498 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
Copyright information: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (