The role of hypoxia-inducible factors in myocardial ischaemia-reperfusion injury and cardioprotection.

In the setting of myocardial ischaemia-reperfusion injury, ischaemia induces severe myocardial hypoxia, whereas the abrupt reintroduction of oxygen during reperfusion further amplifies tissue injury through redox imbalance. This dynamic stabilizes hypoxia-inducible factors (HIFs), which become transcriptionally active and induce hypoxia-responsive gene networks. In turn, HIF-dependent programmes orchestrate adaptive responses to acute hypoxia, including metabolic reprogramming towards glycolysis, promotion of extracellular adenosine signalling, induction of epidermal growth factor pathways and integration with circadian regulatory circuits. Collectively, these programmes increase myocardial resistance to ischaemic stress and limit ischaemia-reperfusion injury. In this Review, we examine the functional roles of HIFs in cardioprotection, with a particular focus on their contributions to ischaemic preconditioning or remote preconditioning and the HIF-dependent pathways that drive these cardioprotective effects. Given that pharmacological HIF stabilizers are already in clinical use for the treatment of renal anaemia, these insights provide a clear translational framework, positioning HIF activation as a plausible and immediately actionable therapeutic approach to prevent or treat myocardial ischaemia-reperfusion injury.