Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α

Chronic intermittent hypoxia (IH), a major feature of obstructive sleep apnea syndrome (OSA), is associated with a more severe myocardial infarction. In this study, we performed RNA sequencing of cardiac samples from mice exposed to IH, which reveals a specific transcriptomic signature of the disease, relative to mitochondrial remodeling and cell death. Corresponding to its activation under chronic IH, we stabilized the Hypoxia Inducible Factor-1 (HIF-1) in cardiac cells in vitro, and observed its association with an increased autophagic flux. In accordance, IH induced autophagy and mitophagy that is decreased in HIF-1+/_ mice compared to wild-type animals suggesting that HIF-1 plays a significant role in IH-induced mitochondrial remodeling. Next, we showed that the AMPK metabolic sensor, typically activated by mitochondrial stress, is inhibited after 3 weeks of IH in hearts. Therefore, we assessed the effect of metformin, an anti-diabetic drug and potent activator of AMPK, on myocardial response to ischemia-reperfusion (I/R) injury. Daily administration of metformin significantly decreases infarct size without any systemic beneficial effect on insulin-resistance under IH conditions. The cardioprotective effect of metformin is lost in AMPK2 knock-out mice demonstrating that AMPK2 isoform promotes metformin-induced cardioprotection in mice exposed to IH. Mechanistically, we found that metformin inhibits IH-induced mitophagy in myocardium and decreases HIF-1 nuclear expression in mice subjected to IH. In vitro demonstrated that metformin induces HIF-1 phosphorylation, decreases its nuclear localization and subsequently HIF-1 transcriptional activity. Collectively, these results identify the AMPK2 metabolic sensor as a novel modulator of HIF-1 activity. Our data suggest that metformin could be considered as a cardioprotective drug in OSA patients independently of their metabolic status.