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论文题目: ROS generated during early reperfusion contribute to intermittent hypobaric hypoxia-afforded cardioprotection against postischemia-induced Ca2+ overload and contractile dysfunction via the JAK2/STAT3 pathway
英文论文题目: ROS generated during early reperfusion contribute to intermittent hypobaric hypoxia-afforded cardioprotection against postischemia-induced Ca2+ overload and contractile dysfunction via the JAK2/STAT3 pathway
第一作者: Wu, L; Tan, JL; Wang, ZH; Chen, YX; Gao, L; Liu, JL; Shi, YH; Endoh, M; Yang, HT
英文第一作者: Wu, L; Tan, JL; Wang, ZH; Chen, YX; Gao, L; Liu, JL; Shi, YH; Endoh, M; Yang, HT
联系作者: Yang, HT (reprint author), Chinese Acad Sci, SIBS, Inst Hlth Sci, Room 1232,Biol Res Bldg A,320 Yue Yang Rd, Shanghai 200031, Peoples R China.
英文联系作者: Yang, HT (reprint author), Chinese Acad Sci, SIBS, Inst Hlth Sci, Room 1232,Biol Res Bldg A,320 Yue Yang Rd, Shanghai 200031, Peoples R China.
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发表年度: 2015
卷: 81
期:
页码: 150-161
摘要: Moderate enhanced reactive oxygen species (ROS) during early reperfusion trigger the cardioprotection against ischemia/reperfusion (I/R) injury, while the mechanism is largely unknown. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) contributes to the cardioprotection but whether it is activated by ROS and how it regulates Ca2+ homeostasis remain unclear. Here we investigated whether the ROS generated during early reperfusion protect the heart/cardiomyocyte against I/R-induced Ca2+ overload and contractile dysfunction via the activation of JAK2/STAT3 signaling pathway by using a cardioprotective model of intermittent hypobaric hypoxia (IHH) preconditioning. IHH improved the postischemic recovery of myocardial contractile performance in isolated rat I/R hearts as well as Ca2+ homeostasis and cell contraction in simulated I/R cardiomyocytes. Meanwhile, IHH enhanced I/R-increased STAT3 phosphorylation at tyrosine 705 in the nucleus and reversed I/R-suppressed STAT3 phosphorylation at serine 727 in the nucleus and mitochondria during reperfusion. Moreover, IHH improved I/R-suppressed sarcoplasmic reticulum (SR) Ca2+-ATPase 2 (SERCA2) activity, enhanced I/R-increased Bcl-2 expression, and promoted the co-localization and interaction of Bcl-2 with SERCA2 during reperfusion. These effects were abolished by scavenging ROS with N-(2-mercaptopropionyI)-glycine (2-MPG) and/or by inhibiting JAK2 with AG490 during the early reperfusion. Furthermore, IHH-improved postischemic SERCA2 activity and Ca2+ homeostasis as well as cell contraction were reversed after Bcl-2 knockdown by short hairpin RNA. In addition, the reversal of the I/R-suppressed mitochondrial membrane potential by IHH was abolished by 2-MPG and AG490. These results indicate that during early reperfusion the ROS/JAK2/STAT3 pathways play a crucial role in (i) the IHH-maintained intracellular Ca2+ homeostasis via the improvement of postischemic SERCA2 activity through the increase of SR Bcl-2 and its interaction with SERCA2; and (ii) the IHH-improved mitochondrial function. (C) 2015 Elsevier Ltd. All rights reserved.
英文摘要: Moderate enhanced reactive oxygen species (ROS) during early reperfusion trigger the cardioprotection against ischemia/reperfusion (I/R) injury, while the mechanism is largely unknown. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) contributes to the cardioprotection but whether it is activated by ROS and how it regulates Ca2+ homeostasis remain unclear. Here we investigated whether the ROS generated during early reperfusion protect the heart/cardiomyocyte against I/R-induced Ca2+ overload and contractile dysfunction via the activation of JAK2/STAT3 signaling pathway by using a cardioprotective model of intermittent hypobaric hypoxia (IHH) preconditioning. IHH improved the postischemic recovery of myocardial contractile performance in isolated rat I/R hearts as well as Ca2+ homeostasis and cell contraction in simulated I/R cardiomyocytes. Meanwhile, IHH enhanced I/R-increased STAT3 phosphorylation at tyrosine 705 in the nucleus and reversed I/R-suppressed STAT3 phosphorylation at serine 727 in the nucleus and mitochondria during reperfusion. Moreover, IHH improved I/R-suppressed sarcoplasmic reticulum (SR) Ca2+-ATPase 2 (SERCA2) activity, enhanced I/R-increased Bcl-2 expression, and promoted the co-localization and interaction of Bcl-2 with SERCA2 during reperfusion. These effects were abolished by scavenging ROS with N-(2-mercaptopropionyI)-glycine (2-MPG) and/or by inhibiting JAK2 with AG490 during the early reperfusion. Furthermore, IHH-improved postischemic SERCA2 activity and Ca2+ homeostasis as well as cell contraction were reversed after Bcl-2 knockdown by short hairpin RNA. In addition, the reversal of the I/R-suppressed mitochondrial membrane potential by IHH was abolished by 2-MPG and AG490. These results indicate that during early reperfusion the ROS/JAK2/STAT3 pathways play a crucial role in (i) the IHH-maintained intracellular Ca2+ homeostasis via the improvement of postischemic SERCA2 activity through the increase of SR Bcl-2 and its interaction with SERCA2; and (ii) the IHH-improved mitochondrial function. (C) 2015 Elsevier Ltd. All rights reserved.
刊物名称: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
英文刊物名称: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
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学科: Cardiovascular System & Cardiology; Cell Biology
英文学科: Cardiovascular System & Cardiology; Cell Biology
影响因子: 4.655
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论文类别: Article
英文论文类别: Article
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