Responses of HIFs to hypoxia or hyperoxia

Under normoxic conditions, hydroxylation at two proline residues by prolyl hydroxylases (PHDs) promotes the association between hypoxia-inducible factor-α (HIFα) and the von Hippel–Lindau (VHL) gene product, leading to HIFα destruction via the ubiquitin–proteasome pathway,,. During hypoxia, this process is suppressed due to the lack of oxygen as a substrate for PHDs, allowing the HIFα subunit to escape proteolysis. After stabilization, HIFα dimerizes with HIF1β, and the heterodimer translocates to the nucleus to activate the transcription of target genes that contain hypoxia response elements (HREs) in their promoter. These target genes control essential physiological functions such as hypoxia adaptation, cell metabolism, inflammation, apoptosis and angiogenesis. Importantly, gene repression by HIFs frequently occurs as an indirect response that involves the transcriptional induction of HIF-dependent microRNAs (miRNAs) and the subsequent repression of target gene expression–. Furthermore, miRNAs have also been shown to participate in a feedforward pathway via an increase in HIF responses through PHD1 repression to provide organ protection during ischaemia–reperfusion injury. HIF stabilization by HIF–PHD inhibitors (such as daprodustat, dimethyloxalylglycine, roxadustat and vadadustat) might be a potential therapeutic approach for acute cardiovascular disease,. In addition, HIF activity is also regulated by hydroxylation of a single conserved asparaginyl residue at the C-terminal transactivation domain by the oxygen-dependent asparaginyl hydroxylase factor inhibiting HIF1 (FIH1). During hyperoxia, high oxygen levels prevent the hypoxic inhibition of PHDs during conditions such as inflammation, ischaemia or metabolic imbalance. Attenuated HIF stabilization can dampen adaptive responses, such as angiogenic responses, or cardioprotection by adenosine generation and signalling (for example, through decreased adenosine A2A receptor signalling). As such, hyperoxia is associated with attenuated adenosine production and signalling, abolished preconditioning of the heart, suppression of adaptive metabolic responses, and reduced capacity of HIFs to dampen inflammation. Of note, given that HIF–PHD inhibitors will still be functional in stabilizing HIFs, even during hyperoxia, HIF activators can be considered as a cardioprotective strategy that works independently of the level of oxygen therapy that a patient receives. DMOG, dimethyloxalylglycine; OH, hydroxylation; Ub, ubiquitination; VEGF, vascular endothelial growth factor.

Publication

Interplay of hypoxia-inducible factors and oxygen therapy in cardiovascular medicine. (2024) Yafen Liang, et al. Nat Rev Cardiol. ;20(11):723-737. Figure: F1. Homo sapiens

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