University of Oulu

Tapio Röning, Johanna Magga, Anna Laitakari, Riikka Halmetoja, Joona Tapio, Elitsa Y. Dimova, Zoltan Szabo, Lea Rahtu-Korpela, Anna Kemppi, Gail Walkinshaw, Johanna Myllyharju, Risto Kerkelä, Peppi Koivunen, Raisa Serpi, Activation of the hypoxia response pathway protects against age-induced cardiac hypertrophy, Journal of Molecular and Cellular Cardiology, Volume 164, 2022, Pages 148-155, ISSN 0022-2828,

Activation of the hypoxia response pathway protects against age-induced cardiac hypertrophy

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Author: Röning, Tapio1; Magga, Johanna2; Laitakari, Anna1;
Organizations: 1Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
2Biocenter Oulu and Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Finland
3FibroGen Inc., San Francisco, CA, USA
4Faculty of Medicine, University of Oulu, Oulu, Finland
5Biobank Borealis of Northern Finland, Oulu University Hospital, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.4 MB)
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Language: English
Published: Elsevier, 2022
Publish Date: 2022-03-09


Aims: We have previously demonstrated protection against obesity, metabolic dysfunction, atherosclerosis and cardiac ischemia in a hypoxia-inducible factor (HIF) prolyl 4-hydroxylase-2 (Hif-p4h-2) deficient mouse line, attributing these protective effects to activation of the hypoxia response pathway in a normoxic environment. We intended here to find out whether the Hif-p4h-2 deficiency affects the cardiac health of these mice upon aging.

Methods and results: When the Hif-p4h-2 deficient mice and their wild-type littermates were monitored during normal aging, the Hif-p4h-2 deficient mice had better preserved diastolic function than the wild type at one year of age and less cardiomyocyte hypertrophy at two years. On the mRNA level, downregulation of hypertrophy-associated genes was detected and shown to be associated with upregulation of Notch signaling, and especially of the Notch target gene and transcriptional repressor Hairy and enhancer-of-split-related basic helix-loop-helix (Hey2). Blocking of Notch signaling in cardiomyocytes isolated from Hif-p4h-2 deficient mice with a gamma-secretase inhibitor led to upregulation of the hypertrophy-associated genes. Also, targeting Hey2 in isolated wild-type rat neonatal cardiomyocytes with siRNA led to upregulation of hypertrophic genes and increased leucine incorporation indicative of increased protein synthesis and hypertrophy. Finally, oral treatment of wild-type mice with a small molecule inhibitor of HIF-P4Hs phenocopied the effects of Hif-p4h-2 deficiency with less cardiomyocyte hypertrophy, upregulation of Hey2 and downregulation of the hypertrophy-associated genes.

Conclusions: These results indicate that activation of the hypoxia response pathway upregulates Notch signaling and its target Hey2 resulting in transcriptional repression of hypertrophy-associated genes and less cardiomyocyte hypertrophy. This is eventually associated with better preserved cardiac function upon aging. Activation of the hypoxia response pathway thus has therapeutic potential for combating age-induced cardiac hypertrophy.

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Series: Journal of molecular and cellular cardiology
ISSN: 0022-2828
ISSN-E: 1095-8584
ISSN-L: 0022-2828
Volume: 164
Pages: 148 - 155
DOI: 10.1016/j.yjmcc.2021.12.003
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Funding: This work was supported by Academy of Finland grants 266719 and 308009 (PK), and 296498 (JMy), the Academy of Finland Center of Excellence 2012–2017 grants 251314 and 284605 (JMy), and grants from the S. Jusélius Foundation (PK and JMy) and the Jane and Aatos Erkko Foundation (PK and JMy).
Academy of Finland Grant Number: 266719
Detailed Information: 266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
296498 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
284605 (Academy of Finland Funding decision)
Copyright information: © 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (