0191 : The increase in myocardial infarct size induced by intermittent hypoxia and HIF-1 activation, is attenuated by endoplasmic reticulum stress inhibition

IntroductionObstructive sleep apnea (OSA) is a highly prevalent disease characterized by repetitive upper airway collapse during sleep leading to chronic intermittent hypoxia (IH). It has been shown in patients that OSA contributes to myocardial infarct expansion. The lack of knowledge about the mechanisms involved in OSA-associated cardiovascular complications had limited the development of specific treatment whereas the gold standard treatment is little tolerated. In the context of cardiomyocytes death or life, this study purposes to investigate the role of endoplasmic reticulum (ER) stress and hypoxia inducible factor-1 (HIF-1) in myocardial susceptibility to ischemia-reperfusion (I/R) induced by chronic IH.MethodsC57Bl6J, HIF-1α+/– and their control mice were exposed to 14 days of IH (21–5% FiO2, 60s cycle, 8h/day). Then, mice were submitted to an in vivo ischemia-reperfusion to assess infarct size (IS, in % relative to area at risk) or hearts were removed to assess ER stress markers and HIF-1 activity using Western-blot and ELISA. In additional groups, TUDCA (an ER stress inhibitor, 75mg. kg-1) was administered daily during N or IH exposition to assess the role of ER stress in IH-susceptibility to I/R.ResultsWhereas chronic IH induced an increase in infarct size (33.7±9.4 vs 61.0±5.6% in N and IH groups, respectively, p<0.05), IH failed to increase infarct size in HIF1α+/- mice (42.4±2.7 vs 24.7±3.4% in HIF1α+/- -N and HIF1α+/- -IH, respectively). An increase in HIF-1 activity and ER stress markers was also observed in IH-mice. By the way, TUDCA totally abolished the IH-increased in infarct size (49.9±3.0 vs 61.0±5.6% in IH-TUDCA, respectively) as well as the IH-increased in HIF-1 activity (1.3±0.04 vs 0.14±0.02 fold increase in IH and IH/TUDCA, p