title: Endoplasmic reticulum stress as a novel inducer of hypoxia inducible factor-1 activity: its role in the susceptibility to myocardial ischemia-reperfusion induced by chronic intermittent hypoxia.
abstract: BACKGROUND
  Obstructive sleep apnea (OSA) is a highly prevalent disease and a risk factor for myocardial infarction expansion in humans. Intermittent hypoxia (IH) is known to be the most important OSA feature in terms of cardiovascular morbi-mortality. Since ER stress and HIF-1 are known to be involved in cardiomyocyte life or death, this study investigates the role of ER stress on HIF-1 activation in myocardial susceptibility to ischemia-reperfusion (I/R) induced by IH.
  
  
  METHODS
  C57Bl6J, HIF-1α(+/-) and their respective control mice were exposed to 14 days of IH (21-5% FiO2, 60 scycle, 8h/day). Myocardial inter-organelle calcium exchanges, ER stress and HIF-1 activity were investigated and in vivo I/R was performed to measure infarct size. In additional groups, tauroursodeoxycholic acid (TUDCA, 75 mg·kg(-1)), an ER stress inhibitor, was administered daily during exposure.
  
  
  RESULTS
  In C57Bl6J mice, chronic IH induced an increase in ER-Ca(2+) content, ER stress markers and HIF-1 activity, associated with an enhanced infarct size (33.7 ± 9.4 vs. 61.0 ± 5.6% in N and IH, respectively, p<0.05). IH failed to increase infarct size in HIF-1α deficient mice (42.4 ± 2.7 and 24.7 ± 3.4% N and IH, respectively). Finally, TUDCA totally abolished the IH-induced increase in HIF-1 activity (1.3 ± 0.04 vs. 0.14 ± 0.02 fold increase in IH vs. IH-TUDCA respectively, p<0.0001) and in infarct size (55.5 ± 7.6 vs. 49.9 ± 3.0 in N-TUDCA and IH-TUDCA, respectively).
  
  
  CONCLUSIONS
  This novel regulatory mechanism of HIF-1 activity by ER stress should be considered as a potential diagnostic tool for cardiovascular complications in OSA patients as well as a therapeutic target to limit myocardial ischemic damage.
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France. Electronic address: elise.belaidi-corsat@ujf-grenoble.fr.
authors.forename: Elise
authors.initials: E
authors.lastname: Belaidi
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourdier
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Moulin
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Lemarié
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Levy
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pépin
authors.affiliation: Université Picardie, Laboratoire de biologie cellulaire moléculaire, Amiens 80000, France.
authors.forename: Irina
authors.initials: I
authors.lastname: Korichneva
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Godin-Ribuot
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble F-38042, France; INSERM, U1042, Grenoble F-38042, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Arnaud
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004790:Enzyme Induction / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D015425:Myocardial Reperfusion / Q000379:methods; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Endoplasmic reticulum stress; Hypoxia inducible factor-1; Intermittent hypoxia; Myocardium