Activation of the hypoxia response pathway protects against age-induced cardiac hypertrophy
Röning, Tapio; Magga, Johanna; Laitakari, Anna; Halmetoja, Riikka; Tapio, Joona; Dimova, Elitsa Y.; Szabo, Zoltan; Rahtu-Korpela, Lea; Kemppi, Anna; Walkinshaw, Gail; Myllyharju, Johanna; Kerkelä, Risto; Koivunen, Peppi; Serpi, Raisa (2021-12-14)
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, https://doi.org/10.1016/j.yjmcc.2021.12.003
© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
https://creativecommons.org/licenses/by/4.0/
https://urn.fi/URN:NBN:fi-fe2022030922677
Tiivistelmä
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.
Kokoelmat
- Avoin saatavuus [32009]