Moulin, Sophie and Thomas, Amandine and Wagner, Stefan and Arzt, Michael and Dubouchaud, Herve and Lamarche, Frederic and Bouyon, Sophie and Vial, Guillaume and Godin-Ribuot, Diane and Pepin, Jean-Louis and Arnaud, Claire and Belaidi, Elise (2022) Intermittent Hypoxia-Induced Cardiomyocyte Death Is Mediated by HIF-1 Dependent MAM Disruption. ANTIOXIDANTS, 11 (8): 1462. ISSN , 2076-3921
Full text not available from this repository. (Request a copy)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-1 alpha, Grp78 and CHOP expressions. Wild-type and HIF-1 alpha(+/-) mice were exposed to normoxia (N) or IH (21-5% O-2, 60 cycles/h, 8 h/day) for 21 days. Expressions of HIF-1 alpha, 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-1 alpha 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-1 alpha(+/-) mice. Similar to what observed under IH, HIF-1 alpha 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ENDOPLASMIC-RETICULUM STRESS; OBSTRUCTIVE SLEEP-APNEA; INDUCIBLE FACTOR-I; MITOCHONDRIA; HEART; CONSEQUENCES; INJURY; ER; ACTIVATION; PREVENTION; sleep disordered breathing; intermittent hypoxia; hypoxia inducible factor-1; mitochondria associated-ER membrane; cardiomyocyte death |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Feb 2024 14:36 |
| Last Modified: | 27 Feb 2024 14:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58035 |
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