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Basic Research in Cardiology

, 114:39 | Cite as

Cardioprotection of post-ischemic moderate ROS against ischemia/reperfusion via STAT3-induced the inhibition of MCU opening

  • Lan Wu
  • Ji-Liang Tan
  • Zhong-Yan Chen
  • Gang HuangEmail author
Original Contribution

Abstract

Enhanced reactive oxygen species (ROS) at the beginning of reperfusion activated signal transducer and activator of transcription 3 (STAT3) in intermittent hypobaric hypoxia (IHH)-afforded cardioprotection against ischemia/reperfusion (I/R). However, its mechanism remains largely unknown. This study aimed to investigate the role and the downstream of STAT3 in exogenous enhanced post-ischemic ROS-induced cardioprotection using the model of moderate hydrogen peroxide postconditioning (H2O2PoC) mimicking endogenous ROS in IHH. Moderate H2O2PoC not only improved the post-ischemic myocardial contractile recovery and reduced the infarct size in isolated rat I/R hearts, but also alleviated mitochondrial calcium overload and ameliorated Ca2+ transients, cell contraction, and mitochondrial membrane potential in rat I/R cardiomyocytes. However, the cardioprotective effects of moderate H2O2PoC were abrogated by Janus kinase 2 (JAK2)/STAT3 inhibitor AG490 in rat hearts as well as adenovirus-delivered short hairpin RNA specific for STAT3 and the opener of mitochondrial calcium uniporter (MCU) spermine in rat cardiomyocytes. Notably, the moderate H2O2PoC-afforded cardioprotection abrogated by spermine could be rescued by STAT3 over-expression with adenovirus in rat I/R cardiomyocytes. Besides, moderate H2O2PoC enhanced mitochondrial STAT3 expression during I/R. A co-localization/interaction of STAT3 or phospho-STAT3ser727 and MCU was observed in rat cardiomyocytes with moderate H2O2PoC at 5 and 30 min of reperfusion but not in rat I/R cardiomyocytes. Further, STAT3 interacted with the N-terminal domain (NTD) of MCU in rat cardiomyocytes with moderate H2O2PoC. These findings indicated that post-ischemic moderate ROS activate STAT3 against cardiac I/R by inhibiting MCU opening via its interaction with the NTD of MCU to alleviate mitochondrial calcium overload.

Keywords

Post-ischemic moderate ROS Hydrogen peroxide postconditioning Mitochondrial Ca2+ concentration Cardiac contraction Signal transducer and activator of transcription 3 Mitochondrial calcium uniporter 

Notes

Acknowledgements

This work was supported by National Natural Sciences Foundation of China (81600246), Shanghai Excellent Young Teachers Funding Project (zzjkyx16004) and Shanghai Municipal Education Commission (Plateau Disciplinary Program for Medical Technology of SUMHS, 2018-2020).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.

Supplementary material

395_2019_747_MOESM1_ESM.pdf (1.3 mb)
Supplementary material 1 (PDF 1341 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Basic Medical Sciences and Shanghai Key Laboratory of Molecular ImagingShanghai University of Medicine and Health SciencesShanghaiChina
  2. 2.Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and HealthShanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS)ShanghaiChina
  3. 3.Department of CardiologyShanghai University of Medicine and Health Sciences Affiliated Zhoupu HospitalShanghaiChina

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