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

Abstract

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 hypertrophyassociated 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-loophelix (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 hypertrophyassociated 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.

Targeting the redox system for cardiovascular regeneration in aging

“…However, dysregulation of HIF-1α signaling in aging impairs the responsiveness of CPCs to hypoxia, leading to compromised cardiac repair mechanisms. Multiple factors contribute to the decline in HIF-1α expression and activity during aging (Röning et al, 2022).…”

“…However, dysregulation of HIF‐1α signaling in aging impairs the responsiveness of CPCs to hypoxia, leading to compromised cardiac repair mechanisms. Multiple factors contribute to the decline in HIF‐1α expression and activity during aging (Röning et al., 2022 ). Accumulating evidence suggests that age‐related changes in the progenitor/stem cell microenvironment, including oxidative stress, chronic inflammation, and cellular senescence, impair HIF‐1α signaling (Marino et al., 2022 ; Sweeney et al., 2022 ).…”

The Inflamm-Aging Model Identifies Key Risk Factors in Atherosclerosis

“…The aging marker related to the most ( Keesey and Powley, 2008 ) disease markers ( Supplementary Tables S13 ) was HEY2, the main sensor of Notch signal transduction. HEY2 has a key role in cardiac development; for example, it protects the heart from age-induced hypertrophic changes ( Röning et al, 2022 ). It also regulates the proliferation of VASCs ( Shirvani et al, 2007 ).…”

Thiol reductive stress activates the hypoxia response pathway

“…The hypoxia response pathway has important roles in health, lifespan, and various pathological conditions. Mice with constitute active hypoxia response pathway are protected against a myriad of pathological conditions, including obesity and metabolic dysfunction (Rahtu-Korpela et al, 2014), cardiac and skeletal muscle ischemia (Hassinen et al, 2010; Karsikas et al, 2016), cardiac hypertrophy (Roning et al, 2022), atherosclerosis (Rahtu-korpela et al, 2016), and alcoholic fatty liver diseases (Laitakari et al, 2019). Activation of the hypoxia response pathway under normoxia conditions increases stress resistance (Bellier et al, 2009), reduces susceptibility to neurodegenerative disease, and increases lifespan (Mehta et al, 2009) in C. elegans .…”