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

Abstract

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.

• Authors: 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
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 164 Pg. 148-155 (03 2022) ISSN: 1095-8584 [Electronic] England
• PMID: 34919895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Hypoxia-Inducible Factor-Proline Dioxygenases

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cardiomegaly (genetics, metabolism)
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases (genetics, metabolism)
• Mice
• Rats
• Signal Transduction