University of Oulu

Laitakari, A, Huttunen, R, Kuvaja, P, et al. Systemic long‐term inactivation of hypoxia‐inducible factor prolyl 4‐hydroxylase 2 ameliorates aging‐induced changes in mice without affecting their life span. The FASEB Journal. 2020; 34: 5590– 5609. https://doi.org/10.1096/fj.201902331R

Systemic long‐term inactivation of hypoxia‐inducible factor prolyl 4‐hydroxylase 2 ameliorates aging‐induced changes in mice without affecting their life span

Saved in:
Author: Laitakari, Anna1; Huttunen, Riikka1; Kuvaja, Paula2,3;
Organizations: 1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
2Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
3Department of Pathology, Oulu University Hospital, Oulu, Finland
44Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
5Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
Format: article
Version: submitted version
Access: open
Online Access: PDF Full Text (PDF, 31 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202102084026
Language: English
Published: John Wiley & Sons, 2020
Publish Date: 2021-02-08
Description:

Abstract

Hypoxia inactivates hypoxia‐inducible factor (HIF) prolyl 4‐hydroxylases (HIF‐P4Hs), which stabilize HIF and upregulate genes to restore tissue oxygenation. HIF‐P4Hs can also be inhibited by small molecules studied in clinical trials for renal anemia. Knowledge of systemic long‐term inactivation of HIF‐P4Hs is limited but crucial, since HIF overexpression is associated with cancers. We aimed to determine the effects of systemic genetic inhibition of the most abundant isoenzyme HIF prolyl 4‐hydroxylase‐2 (HIF‐P4H‐2)/PHD2/EglN1 on life span and tissue homeostasis in aged mice. Our data showed no difference between wild‐type and HIF‐P4H‐2‐deficient mice in the average age reached. There were several differences, however, in the primary causes of death and comorbidities, the HIF‐P4H‐2‐deficient mice having less inflammation, liver diseases, including cancer, and myocardial infarctions, and not developing anemia. No increased cancer incidence was observed due to HIF‐P4H‐2‐deficiency. These data suggest that chronic inactivation of HIF‐P4H‐2 is not harmful but rather improves the quality of life in senescence.

see all

Series: The FASEB journal
ISSN: 0892-6638
ISSN-E: 1530-6860
ISSN-L: 0892-6638
Volume: 34
Issue: 4
Pages: 5590 - 5609
DOI: 10.1096/fj.201902331R
OADOI: https://oadoi.org/10.1096/fj.201902331R
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
HCC
Funding: This study was supported by Academy of Finland grants 266719 and 308009 (P. Koivunen), and 296498 (JM), the Academy of Finland Center of Excellence 2012‐2017 grant 251314 (JM), and grants from the S. Jusélius Foundation (P. Koivunen and JM), the Finnish Cancer Organization (P. Koivunen), and the Jane and Aatos Erkko Foundation (P. Koivunen and JM) and FibroGen Inc. (JM).
Academy of Finland Grant Number: 266719
308009
296498
Detailed Information: 266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
296498 (Academy of Finland Funding decision)
Copyright information: © 2020 Federation of American Societies for Experimental Biology. This is the submitted version of the following article: Laitakari, A, Huttunen, R, Kuvaja, P, et al. Systemic long‐term inactivation of hypoxia‐inducible factor prolyl 4‐hydroxylase 2 ameliorates aging‐induced changes in mice without affecting their life span. The FASEB Journal. 2020; 34: 5590– 5609, which has been published in final form at https://doi.org/10.1096/fj.201902331R.