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

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• 作者：Elise Belaidi<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>elise.belaidi-corsat@ujf-grenoble.fr" class="auth_mail" title="E-mail the corresponding authorsup> ; Amandine Thomas<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>1sup> ; Guillaume Bourdier<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>1sup> ; Sophie Moulin<sup>asup><sup> ; sup><sup>bsup> ; Emeline Lemarié ; <sup>asup><sup> ; sup><sup>bsup> ; Patrick Levy<sup>asup><sup> ; sup><sup>bsup> ; Jean-Louis Pé ; pin<sup>asup><sup> ; sup><sup>bsup> ; Irina Korichneva<sup>csup> ; Diane Godin-Ribuot<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>2sup> ; Claire Arnaud<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>2sup>
• 关键词：Intermittent hypoxia ; Myocardium ; Endoplasmic reticulum stress ; Hypoxia inducible factor-1
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：210
• 期：Complete
• 页码：45-53
• 全文大小：1645 K

文摘

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.

sp0045">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.

sSec_2">Methods

sp0050">C57Bl6J, HIF-1α<sup>+/‐sup> and their respective control mice were exposed to 14 days of IH (21&ndash;5% FiO<sub>2sub>, 60 s 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<sup>‐ 1sup>), an ER stress inhibitor, was administered daily during exposure.

sSec_3">Results

sp0055">In C57Bl6J mice, chronic IH induced an increase in ER-Ca<sup>2 +sup> content, ER stress markers and HIF-1 activity, associated with an enhanced infarct size (33.7 &plusmn; 9.4 vs. 61.0 &plusmn; 5.6% in N and IH, respectively, p < 0.05). IH failed to increase infarct size in HIF-1α deficient mice (42.4 &plusmn; 2.7 and 24.7 &plusmn; 3.4% N and IH, respectively). Finally, TUDCA totally abolished the IH-induced increase in HIF-1 activity (1.3 &plusmn; 0.04 vs. 0.14 &plusmn; 0.02 fold increase in IH vs. IH-TUDCA respectively, p < 0.0001) and in infarct size (55.5 &plusmn; 7.6 vs. 49.9 &plusmn; 3.0 in N-TUDCA and IH-TUDCA, respectively).

sSec_4">Conclusion

sp0060">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.