Aurones as new modulators of hypoxia inducible factor-1 (HIF-1) to prevent cardiac cell death

Myocardial infarction (MI) is the leading cause of death worldwide. The extent of infarct size, determined by the degree of cardiomyocyte death, is a major factor in post-MI functional recovery. Therefore, cardioprotective strategies focus on limiting infarct size. Among the mechanisms involved in the MI response, Hypoxia Inducible Factor-1 (HIF-1) plays a complex role that can be either beneficial or detrimental depending on the nature of its activation ( i.e., acute or chronic ). Given the potential cardioprotective effects of curcumin through HIF-1 modulation, we investigated the impact of hydroxylated aurone derivatives on cardiomyoblasts (H9C2) incubated with cobalt chloride (CoCl₂, 1 mM for 2 h), which mimics hypoxia by stabilizing HIF-1α. Cell viability was measured using the methyl thiazolyl tetrazolium (MTT) assay, and HIF-1α expression was assessed by western blot. Interestingly, only the three 7-hydroxyaurones enhanced cell viability under CoCl₂-induced stress, showing efficiencies comparable to curcumin (120–140 % improvement at 100 μM). However, they exhibited divergent effects on HIF-1α expression: 2′- and 3′-hydroxyaurones led to a reduction, whereas 4′-hydroxyaurone caused an increase. This study thus identifies a new class of molecules capable of modulating HIF-1 activity and preventing cardiac cell death. These findings open new perspectives, as these aurones could potentially be developed for strategies aiming to reduce infarct size by regulating HIF-1 expression, either increasing HIF-1α in the context of MI alone or suppressing its expression under chronic conditions such as obstructive sleep apnea syndrome (OSA). • Myocardial infarction and heart failure remain leading factors in global mortality. • Preventive treatments are needed to adress the root causes of these pathologies. • HIF-1α is a key in intermittent hypoxia, the main feature of these pathologies. • Aurones modulate HIF-1α expression and therefore intermittent hypoxia.