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. (April 2015)

• Record Type: Journal Article
• Authors: Wu, Lan; Tan, Ji-Liang; Wang, Zhi-Hua; Chen, Yi-Xiong; Gao, Ling; Liu, Jin-Long; Shi, Yun-Hua; Endoh, Masao; Yang, Huang-Tian
• Is Part Of: Journal of molecular and cellular cardiology. Volume 81(2015:Apr.)
• Page Start: 150
• Page End: 161
• Publication Date: 2015-04
• Subjects: Reactive oxygen species -- Intracellular Ca2 + concentration -- STAT3 -- Bcl-2 -- SR Ca2 +-ATPase 2 -- Intermittent hypobaric hypoxia; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.02.015
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: 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 Ca 2 + homeostasis remain unclear. Here we investigated whether the ROS generated during early reperfusion protect the heart/cardiomyocyte against I/R-induced Ca 2 + 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 Ca 2 + 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) Ca 2 + -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-mercaptopropionyl)-glycine (2-MPG) and/or by inhibiting JAK2 with AG490 during the early reperfusion. Furthermore, IHH-improved postischemic SERCA2 activity and Ca 2 + 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 Ca 2 + 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. Graphical abstract: Ischematic representation of proposed mechanisms underlying the cardioprotection of intermittent hypobaric hypoxia (IHH) against ischemia/reperfusion injury through the ROS/STAT3 signaling pathway. pY-STAT3, phospho-STAT3 tyr705 ; pS-STAT3, phospho-STAT3 ser727 . Red arrow, IHH-induced responses; black arrow, ischemia/reperfusion-induced responses. Up thick arrow, increases; up thin arrow, recovery; down arrow, decreases. Highlights: IHH improves postischemic Ca 2 + overload and contraction via ROS/JAK2/STAT3 pathways. IHH enhances postischemic phospho-STAT3 via the ROS generated at early reperfusion. SR Bcl-2 contributes to the IHH-improved SERCA2 activity via ROS/JAK2/STAT3 pathways. ROS/JAK2/STAT3 mediate the cardioprotection of IHH on the mitochondrial function.