Cardioprotection of post-ischemic moderate ROS against ischemia/reperfusion via STAT3-induced the inhibition of MCU opening
Autor: | Zhong-yan Chen, Jiliang Tan, Lan Wu, Gang Huang |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Male STAT3 Transcription Factor Physiology Ischemia Myocardial Ischemia Spermine Myocardial Reperfusion Injury 030204 cardiovascular system & hematology Mitochondria Heart Small hairpin RNA Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Physiology (medical) medicine Animals Myocytes Cardiac STAT3 Cardioprotection chemistry.chemical_classification Reactive oxygen species Janus kinase 2 biology Chemistry medicine.disease Cell biology Rats 030104 developmental biology Ischemic Preconditioning Myocardial biology.protein STAT protein Calcium Channels Cardiology and Cardiovascular Medicine Reactive Oxygen Species Signal Transduction |
Zdroj: | Basic research in cardiology. 114(5) |
ISSN: | 1435-1803 |
Popis: | 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. |
Databáze: | OpenAIRE |
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