bims-oxygme 2025-05-18 papers

Issue of 2025–05–18
three papers selected by
Onurkan Karabulut, Berkeley City College

Cells. 2025 May 04. pii: 673. [Epub ahead of print]14(9):

The Distinct Role of HIF-1α and HIF-2α in Hypoxia and Angiogenesis.

Mouayad Zuheir Bakleh, Ayman Al Haj Zen.

Hypoxia results in a wide range of adaptive physiological responses, including metabolic reprogramming, erythropoiesis, and angiogenesis. The response to hypoxia at the cellular level is mainly regulated by hypoxia-inducible factors (HIFs): HIF1α and HIF2α isoforms. Although structurally similar and overlapping gene targets, both isoforms can exhibit distinct expression patterns and functions in some conditions of hypoxia. The interaction between these isoforms, known as the "HIF switch", determines their coordinated function under varying oxygen levels and exposure time. In angiogenesis, HIF-1α is rapidly stabilized under acute hypoxia, prompting a metabolic shift from oxidative phosphorylation to glycolysis and initiating angiogenesis by activating endothelial cells and extracellular matrix remodeling. Conversely, HIF-2α regulates cell responses to chronic hypoxia by sustaining genes critical for vascular remodeling and maturation. The current review highlights the different roles and regulatory mechanisms of HIF-1α and HIF-2α isoforms, focusing on their involvement in cell metabolism and the multi-step process of angiogenesis. Tuning the specific targeting of HIF isoforms and finding the right therapeutic window is essential to obtaining the best therapeutic effect in diseases such as cancer and vascular ischemic diseases.

Keywords: HIF signaling; HIF switch; angiogenesis; hypoxia

DOI: https://doi.org/10.3390/cells14090673

Redox Biol. 2025 May 06. pii: S2213-2317(25)00179-X. [Epub ahead of print]83 103666

Hypoxia in multiple sclerosis.

Johannes Burtscher, Robert W Motl, Klaus Berek, Hannelore Ehrenreich, Martin Kopp, Erich Hohenauer.

Low oxygen availability (hypoxia) is a prominent but poorly understood feature in multiple sclerosis (MS). Whether hypoxia causes or drives MS pathology and symptoms or whether it is a consequence of other pathological events, such as inflammation and vascular dysfunction, is unknown. Here, we summarize the available literature on the interplay between hypoxia and both pathological and symptomatic features of MS. Severe environmental hypoxia (i.e., altitude) may trigger or facilitate MS-related events, possibly by exacerbating tissue hypoxia in the central nervous system. Accordingly, increasing oxygen supply can mitigate pathological and clinical parameters in MS models. In contrast, stimulating the endogenous hypoxia response and adaptation systems by controlled exposure to hypoxia (hypoxia conditioning) renders the central nervous system more resistant to hypoxic insults, thereby attenuating pathology and symptomatology in MS models. Overlapping mechanisms likely play a role in the benefits conferred by physical activity in MS. We provide an integrative model to explain the paradoxically beneficial outcomes of both increased and decreased ambient oxygen conditions. In conclusion, controlled exposure to hypoxia, perhaps in combination with exercise, is a promising, possibly disease-course modifying therapeutic approach for MS. However, many open questions remain.

Keywords: Hypoxia inducible factor; Mitochondria; Neurodegeneration; Neuroinflammation; Oxidative stress; Oxygen sensing

DOI: https://doi.org/10.1016/j.redox.2025.103666

FEBS J. 2025 May 13.

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

Sophie Moulin, Britanny Blachot-Minassian, Anita Kneppers, Amandine Thomas, Stéphanie Paradis, Laurent Bultot, Claire Arnaud, Jean-Louis Pépin, Luc Bertrand, Rémi Mounier, Elise Belaidi.

Chronic intermittent hypoxia (IH), a major feature of obstructive sleep apnea syndrome (OSA), is associated with greater severity of 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-1α (HIF-1α) in cardiac cells in vitro and observed its association with an increased autophagic flux. In accordance, IH induced autophagy and mitophagy, which are decreased in HIF-1α+/- 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 was lost in AMPKα2 knock-out mice, demonstrating that AMPKα2 isoform promotes metformin-induced cardioprotection in mice exposed to IH. Mechanistically, we found that metformin inhibits IH-induced mitophagy in myocardium and decreases HIF-1α nuclear expression in mice subjected to IH. In vitro experiments demonstrated that metformin induced HIF-1α phosphorylation, decreased its nuclear localization, and HIF-1 transcriptional activity. Collectively, these results identify the AMPKα2 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.

Keywords: AMPK; HIF‐1; intermittent hypoxia; ischemia–reperfusion; myocardium

DOI: https://doi.org/10.1111/febs.70110