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Open AccessArticle

Intermittent Hypoxia Prevents Myocardial Mitochondrial Ca2+ Overload and Cell Death during Ischemia/Reperfusion: The Role of Reactive Oxygen Species

1
Department of Surgery, Buddhist Tzu Chi General Hospital, Hualien 97002, Taiwan
2
School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
3
Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan
4
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
5
Division of Cardiology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Hualien 97002, Taiwan
6
Master Program in Medical Physiology, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
7
Department of Physiology, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
*
Author to whom correspondence should be addressed.
Cells 2019, 8(6), 564; https://doi.org/10.3390/cells8060564
Received: 6 May 2019 / Revised: 1 June 2019 / Accepted: 5 June 2019 / Published: 9 June 2019
It has been documented that reactive oxygen species (ROS) contribute to oxidative stress, leading to diseases such as ischemic heart disease. Recently, increasing evidence has indicated that short-term intermittent hypoxia (IH), similar to ischemia preconditioning, could yield cardioprotection. However, the underlying mechanism for the IH-induced cardioprotective effect remains unclear. The aim of this study was to determine whether IH exposure can enhance antioxidant capacity, which contributes to cardioprotection against oxidative stress and ischemia/reperfusion (I/R) injury in cardiomyocytes. Primary rat neonatal cardiomyocytes were cultured in IH condition with an oscillating O2 concentration between 20% and 5% every 30 min. An MTT assay was conducted to examine the cell viability. Annexin V-FITC and SYTOX green fluorescent intensity and caspase 3 activity were detected to analyze the cell death. Fluorescent images for DCFDA, Fura-2, Rhod-2, and TMRM were acquired to analyze the ROS, cytosol Ca2+, mitochondrial Ca2+, and mitochondrial membrane potential, respectively. RT-PCR, immunocytofluorescence staining, and antioxidant activity assay were conducted to detect the expression of antioxidant enzymes. Our results show that IH induced slight increases of O2· and protected cardiomyocytes against H2O2- and I/R-induced cell death. Moreover, H2O2-induced Ca2+ imbalance and mitochondrial membrane depolarization were attenuated by IH, which also reduced the I/R-induced Ca2+ overload. Furthermore, treatment with IH increased the expression of Cu/Zn SOD and Mn SOD, the total antioxidant capacity, and the activity of catalase. Blockade of the IH-increased ROS production abolished the protective effects of IH on the Ca2+ homeostasis and antioxidant defense capacity. Taken together, our findings suggest that IH protected the cardiomyocytes against H2O2- and I/R-induced oxidative stress and cell death through maintaining Ca2+ homeostasis as well as the mitochondrial membrane potential, and upregulation of antioxidant enzymes. View Full-Text
Keywords: intermittent hypoxia; mitochondria; Ca2+, ROS; antioxidant intermittent hypoxia; mitochondria; Ca2+, ROS; antioxidant
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Chang, J.-C.; Lien, C.-F.; Lee, W.-S.; Chang, H.-R.; Hsu, Y.-C.; Luo, Y.-P.; Jeng, J.-R.; Hsieh, J.-C.; Yang, K.-T. Intermittent Hypoxia Prevents Myocardial Mitochondrial Ca2+ Overload and Cell Death during Ischemia/Reperfusion: The Role of Reactive Oxygen Species. Cells 2019, 8, 564.

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