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Canadian Journal of Cardiology

Cooperation Between Hypoxia-Inducible Factor 1α and Activating Transcription Factor 4 in Sleep Apnea–Mediated Myocardial Injury

  • Sophie Moulin
    Affiliations
    Laboratoire HP2, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Grenoble, France

    Institut National de la Santé et de la Recherche Médicale U1042, Grenoble, France
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  • Amandine Thomas
    Affiliations
    Laboratoire HP2, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Grenoble, France

    Institut National de la Santé et de la Recherche Médicale U1042, Grenoble, France
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  • Claire Arnaud
    Affiliations
    Laboratoire HP2, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Grenoble, France

    Institut National de la Santé et de la Recherche Médicale U1042, Grenoble, France
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  • Michael Arzt
    Affiliations
    Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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  • Stefan Wagner
    Affiliations
    Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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  • Lars S. Maier
    Affiliations
    Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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  • Jean-Louis Pépin
    Affiliations
    Laboratoire HP2, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Grenoble, France

    Institut National de la Santé et de la Recherche Médicale U1042, Grenoble, France

    Centre Hospitalier Universitaire des Alpes, Grenoble, France
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  • Diane Godin-Ribuot
    Affiliations
    Laboratoire HP2, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Grenoble, France

    Institut National de la Santé et de la Recherche Médicale U1042, Grenoble, France
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  • Author Footnotes
    ‡ These authors contributed equally to this work as senior authors.
    Jonathan Gaucher
    Correspondence
    Corresponding authors: Drs Elise Belaidi and Jonathan Gaucher, Université Grenoble Alpes–Inserm–Laboratoire HP2, Bâtiment Jean Roget, Faculté de Médecine—Pharmacie, Domaine de la Merci, 38042 Grenoble, France. Tel.: +33-476-637-108; fax: +33-476-637-178.
    Footnotes
    ‡ These authors contributed equally to this work as senior authors.
    Affiliations
    Laboratoire HP2, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Grenoble, France

    Institut National de la Santé et de la Recherche Médicale U1042, Grenoble, France
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this work as senior authors.
    Elise Belaidi
    Correspondence
    Corresponding authors: Drs Elise Belaidi and Jonathan Gaucher, Université Grenoble Alpes–Inserm–Laboratoire HP2, Bâtiment Jean Roget, Faculté de Médecine—Pharmacie, Domaine de la Merci, 38042 Grenoble, France. Tel.: +33-476-637-108; fax: +33-476-637-178.
    Footnotes
    ‡ These authors contributed equally to this work as senior authors.
    Affiliations
    Laboratoire HP2, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Grenoble, France

    Institut National de la Santé et de la Recherche Médicale U1042, Grenoble, France
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this work as senior authors.
Published:April 13, 2020DOI:https://doi.org/10.1016/j.cjca.2020.04.002

      Abstract

      Chronic intermittent hypoxia (CIH) occurring during sleep apnea amplifies infarct size owing to ischemia-reperfusion. CIH activates hypoxia-inducible factor 1 (HIF-1) and activating transcription factor 4 (ATF4). However, whether HIF-1 and ATF4 interact to promote cardiomyocyte death remains unexplored. For the first time, we observed that in myocardium from apneic patients, CCAAT enhancer–binding protein homologous protein (CHOP) expression is increased and HIF-1α expression is correlated with sleep apnea severity. In mice, single-allele deletion of HIF-1α prevents CIH increase in CHOP expression and infarct size. We uncovered a physical interaction between HIF-1α and ATF4 in CIH that may represent a novel cardiomyocyte death complex.

      Résumé

      L'hypoxie intermittente chronique (HIC), qui se est une conséquence du syndrome d'apnées du sommeil augmente la taille de l'infarctus. La HIC est connue pour activer l'hypoxia inducible factor-1 (HIF-1) et l’activating transcription factor 4 (ATF4). Cependant, l'existence d'un lien entre HIF-1 et ATF4 dans l'induction pouvant conduire à la mort des cardiomyocytes reste inexplorée. Pour la première fois, nous avons observé que dans le myocarde de patients apnéiques, l'expression de CCAAT enhancer-binding protein homologous protein (CHOP) est augmentée et que l'expression de HIF-1 est corrélée avec la sévérité du syndrome d'apnées du sommeil. Chez la souris, la délétion d'un allèle de HIF-1α empêche l'augmentation de l'expression de CHOP et de la taille de l'infarctus. Dans le cadre d’une HIC, nous avons découvert une interaction physique entre HIF-1α et ATF4 qui pourrait représenter un nouveau complexe impliqué dans la mort cellulaire des cardiomyocytes.
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      Linked Article

      • Sleep Apnea, Intermittent Hypoxemia, and Effects on Ischemic Myocardial Damage: Friend or Foe?
        Canadian Journal of CardiologyVol. 36Issue 6
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          Sleep apnea is strongly associated with coronary artery disease, hypertension, heart failure, atrial fibrillation, and sudden death.1-4 In the setting of acute myocardial infarction, the presence of sleep apnea is associated with less myocardial salvage and a smaller reduction in infarct size during recovery.5 Several animal models mimicking chronic intermittent hypoxia as one of the key features of sleep apnea have demonstrated an increased infarct size on ischemia-reperfusion injury,6,7 making chronic intermittent hypoxia a prominent modifier of ischemic myocardial damage.
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