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Alpha7 nicotinic acetylcholine receptor activation protects against myocardial reperfusion injury through modulation of autophagy.

Authors
  • Hou, Zuoxu1
  • Zhou, Yaguang2
  • Yang, Hongyan1
  • Liu, Yan3
  • Mao, Xuechao1
  • Qin, Xinghua1
  • Li, Xiaoliang4
  • Zhang, Xing5
  • Hu, Yuanyuan6
  • 1 Department of Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China. , (China)
  • 2 Department of Physiology, Fourth Military Medical University, Xi'an 710032, China. , (China)
  • 3 Department of Prosthodontics, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China. , (China)
  • 4 Department of Emergency Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. , (China)
  • 5 Department of Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address: [email protected] , (China)
  • 6 College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710032, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Biochemical and Biophysical Research Communications
Publisher
Elsevier
Publication Date
Jun 02, 2018
Volume
500
Issue
2
Pages
357–364
Identifiers
DOI: 10.1016/j.bbrc.2018.04.077
PMID: 29665360
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Alpha7 nicotinic acetylcholine receptor (α7nAChR) activation alleviates myocardial ischemia/reperfusion (MI/R) injury. However, the underlying mechanisms remain unclear. Here, we investigated the role of autophagy in α7nAChR-mediated cardioprotection and the molecular mechanisms involved. Activating α7nAChR with PNU-282987 at the initiation of reperfusion reduced myocardial infarct size in MI/R rats. PNU-282987 treatment also significantly inhibited MI/R-induced myocardial autophagy dysfunction as evidenced by the reduction of LC3-II/LC3-I ratio, Beclin-1 and p62 abundance. In addition, PNU-282987 treatment reduced hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury in vitro, accompanied with the inhibition of Beclin-1-associated autophagy and the restoration of autophagic flux. Interestingly, inhibiting autophagic flux attenuated α7nAChR-afforded improvement of mitochondrial function as well as inhibition of apoptosis in vitro. Mechanistically, co-administration of PNU-282987 with LY294002 (a PI3K inhibitor), AG490 (a JAK2 inhibitor) or Bcl-2 siRNA, but not compound C (an AMPK inhibitor), reduced Bcl-2 level and prevented the modulation of autophagy afforded by PNU-282987 in H/R cardiomyocytes. Collectively, these findings suggest that α7nAChR activation inhibits Beclin-1-associated autophagy dysfunction via the JAK2/Bcl-2 and PI3K/Bcl-2 cascades, leading to cardioprotection against MI/R injury. Copyright © 2018 Elsevier Inc. All rights reserved.

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