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 , 60s cycle, 8 h/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). Conclusion 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.