PMID- 29314656
OWN - NLM
STAT- MEDLINE
DCOM- 20191021
LR  - 20240315
IS  - 1582-4934 (Electronic)
IS  - 1582-1838 (Print)
IS  - 1582-1838 (Linking)
VI  - 22
IP  - 3
DP  - 2018 Mar
TI  - Mammalian target of rapamycin inhibition attenuates myocardial 
      ischaemia-reperfusion injury in hypertrophic heart.
PG  - 1708-1719
LID - 10.1111/jcmm.13451 [doi]
AB  - Pathological cardiac hypertrophy aggravated myocardial infarction and is causally 
      related to autophagy dysfunction and increased oxidative stress. Rapamycin is an 
      inhibitor of serine/threonine kinase mammalian target of rapamycin (mTOR) 
      involved in the regulation of autophagy as well as oxidative/nitrative stress. 
      Here, we demonstrated that rapamycin ameliorates myocardial ischaemia reperfusion 
      injury by rescuing the defective cytoprotective mechanisms in hypertrophic heart. 
      Our results showed that chronic rapamycin treatment markedly reduced the 
      phosphorylated mTOR and ribosomal protein S6 expression, but not Akt in both 
      normal and aortic-banded mice. Moreover, chronic rapamycin treatment 
      significantly mitigated TAC-induced autophagy dysfunction demonstrated by 
      prompted Beclin-1 activation, elevated LC3-II/LC3-I ratio and increased 
      autophagosome abundance. Most importantly, we found that MI/R-induced myocardial 
      injury was markedly reduced by rapamycin treatment manifested by the inhibition 
      of myocardial apoptosis, the reduction of myocardial infarct size and the 
      improvement of cardiac function in hypertrophic heart. Mechanically, rapamycin 
      reduced the MI/R-induced iNOS/gp91(phox) protein expression and decreased the 
      generation of NO and superoxide, as well as the cytotoxic peroxynitrite. 
      Moreover, rapamycin significantly mitigated MI/R-induced endoplasmic reticulum 
      stress and mitochondrial impairment demonstrated by reduced Caspase-12 activity, 
      inhibited CHOP activation, decreased cytoplasmic Cyto-C release and preserved 
      intact mitochondria. In addition, inhibition of mTOR also enhanced the 
      phosphorylated ERK and eNOS, and inactivated GSK3beta, a pivotal downstream target 
      of Akt and ERK signallings. Taken together, these results suggest that mTOR 
      signalling protects against MI/R injury through autophagy induction and 
      ERK-mediated antioxidative and anti-nitrative stress in mice with hypertrophic 
      myocardium.
CI  - (c) 2018 The Authors. Journal of Cellular and Molecular Medicine published by John 
      Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
FAU - Ma, Lei-Lei
AU  - Ma LL
AD  - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute 
      of Biomedical Science, Fudan University, Shanghai, China.
AD  - Department of Critical Care Medicine, Zhejiang Provincial People's Hospital and 
      People's Hospital of Hangzhou Medical College, Hangzhou, China.
FAU - Ma, Xin
AU  - Ma X
AD  - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute 
      of Biomedical Science, Fudan University, Shanghai, China.
FAU - Kong, Fei-Juan
AU  - Kong FJ
AUID- ORCID: 0000-0001-8001-5365
AD  - Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, 
      Tongji University School of Medicine, Shanghai, China.
FAU - Guo, Jun-Jie
AU  - Guo JJ
AD  - Department of Cardiology, Affiliated Hospital of Qingdao University, Qingdao, 
      China.
FAU - Shi, Hong-Tao
AU  - Shi HT
AD  - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute 
      of Biomedical Science, Fudan University, Shanghai, China.
FAU - Zhu, Jian-Bing
AU  - Zhu JB
AD  - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute 
      of Biomedical Science, Fudan University, Shanghai, China.
FAU - Zou, Yun-Zeng
AU  - Zou YZ
AD  - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute 
      of Biomedical Science, Fudan University, Shanghai, China.
FAU - Ge, Jun-Bo
AU  - Ge JB
AUID- ORCID: 0000-0002-8318-4882
AD  - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute 
      of Biomedical Science, Fudan University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180104
PL  - England
TA  - J Cell Mol Med
JT  - Journal of cellular and molecular medicine
JID - 101083777
RN  - 0 (Immunosuppressive Agents)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Autophagy/drug effects
MH  - Cardiomegaly/*complications
MH  - Immunosuppressive Agents/pharmacology
MH  - Male
MH  - Mice
MH  - Myocardial Reperfusion Injury/complications/metabolism/*prevention & control
MH  - Phosphorylation/drug effects
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
PMC - PMC5824378
OTO - NOTNLM
OT  - cardiac hypertrophy
OT  - cardioprotection
OT  - ischaemia reperfusion injury
OT  - oxidative stress
OT  - rapamycin
EDAT- 2018/01/10 06:00
MHDA- 2019/10/23 06:00
PMCR- 2018/03/01
CRDT- 2018/01/10 06:00
PHST- 2017/06/29 00:00 [received]
PHST- 2017/10/06 00:00 [accepted]
PHST- 2018/01/10 06:00 [pubmed]
PHST- 2019/10/23 06:00 [medline]
PHST- 2018/01/10 06:00 [entrez]
PHST- 2018/03/01 00:00 [pmc-release]
AID - JCMM13451 [pii]
AID - 10.1111/jcmm.13451 [doi]
PST - ppublish
SO  - J Cell Mol Med. 2018 Mar;22(3):1708-1719. doi: 10.1111/jcmm.13451. Epub 2018 Jan 
      4.