Dataset Information

Intermittent Hypoxia-Induced Cardiomyocyte Death Is Mediated by HIF-1 Dependent MAM Disruption.

ABSTRACT:

Rationale

Intermittent hypoxia (IH) is one of the main features of sleep-disordered breathing (SDB). Recent findings indicate that hypoxia inducible factor-1 (HIF-1) promotes cardiomyocytes apoptosis during chronic IH, but the mechanisms involved remain to be elucidated. Here, we hypothesize that IH-induced ER stress is associated with mitochondria-associated ER membrane (MAM) alteration and mitochondrial dysfunction, through HIF-1 activation.

Methods

Right atrial appendage biopsies from patients with and without SDB were used to determine HIF-1α, Grp78 and CHOP expressions. Wild-type and HIF-1α^+/- mice were exposed to normoxia (N) or IH (21-5% O₂, 60 cycles/h, 8 h/day) for 21 days. Expressions of HIF-1α, Grp78 and CHOP, and apoptosis, were measured by Western blot and immunochemistry. In isolated cardiomyocytes, we examined structural integrity of MAM by proximity ligation assay and their function by measuring ER-to-mitochondria Ca²⁺ transfer by confocal microscopy. Finally, we measured mitochondrial respiration using oxygraphy and calcium retention capacity (CRC) by spectrofluorometry. MAM structure was also investigated in H9C2 cells incubated with 1 mM CoCl₂, a potent HIF-1α inducer.

Results

In human atrial biopsies and mice, IH induced HIF-1 activation, ER stress and apoptosis. IH disrupted MAM, altered Ca²⁺ homeostasis, mitochondrial respiration and CRC. Importantly, IH had no effect in HIF-1α^+/- mice. Similar to what observed under IH, HIF-1α overexpression was associated with MAM alteration in H9C2.

Conclusion

IH-induced ER stress, MAM alterations and mitochondrial dysfunction were mediated by HIF-1; all these intermediate mechanisms ultimately inducing cardiomyocyte apoptosis. This suggests that HIF-1 modulation might limit the deleterious cardiac effects of SDB.

SUBMITTER: Moulin S

PROVIDER: S-EPMC9405320 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

Intermittent Hypoxia-Induced Cardiomyocyte Death Is Mediated by HIF-1 Dependent MAM Disruption.

Moulin Sophie S Thomas Amandine A Wagner Stefan S Arzt Michael M Dubouchaud Hervé H Lamarche Frédéric F Bouyon Sophie S Vial Guillaume G Godin-Ribuot Diane D Pépin Jean-Louis JL Arnaud Claire C Belaidi Elise E

Antioxidants (Basel, Switzerland) 20220727 8

<h4>Rationale</h4>Intermittent hypoxia (IH) is one of the main features of sleep-disordered breathing (SDB). Recent findings indicate that hypoxia inducible factor-1 (HIF-1) promotes cardiomyocytes apoptosis during chronic IH, but the mechanisms involved remain to be elucidated. Here, we hypothesize that IH-induced ER stress is associated with mitochondria-associated ER membrane (MAM) alteration and mitochondrial dysfunction, through HIF-1 activation.<h4>Methods</h4>Right atrial appendage biopsi ...[more]

PMID: 36009181

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Dataset Information

Intermittent Hypoxia-Induced Cardiomyocyte Death Is Mediated by HIF-1 Dependent MAM Disruption.

Rationale

Methods

Results

Conclusion

Publications

Intermittent Hypoxia-Induced Cardiomyocyte Death Is Mediated by HIF-1 Dependent MAM Disruption.

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