Activation of the hypoxia response pathway protects against age-induced cardiac hypertrophy. (March 2022)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of molecular and cellular cardiology. Volume 164(2022)
• Page Start: 148
• Page End: 155
• Publication Date: 2022-03
• Subjects: Hypoxia -- Hypoxia-inducible-factor -- Notch signaling -- Cardiac hypertrophy -- Aging; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.12.003
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Graphical abstract: Image 1 Highlights: Activation of hypoxia response upregulates Notch signaling and Hey2 in heart. Hif-p4h-2 deficiency associates with less cardiomyocyte hypertrophy upon aging. Blocking of Notch signaling and Hey2 in cardiomyocytes upregulates hypertrophy genes. Small molecule inhibition of HIF-P4Hs leads to less cardiomyocyte hypertrophy.