Mammalian target of rapamycin inhibition attenuates myocardial
ischaemia–reperfusion injury in hypertrophic heart
a, b, #
, Xin Ma
, Fei-Juan Kong
, Jun-Jie Guo
, Hong-Tao Shi
, Yun-Zeng Zou
*, Jun-Bo Ge
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University,
Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital and People’s Hospital of Hangzhou Medical
College, Hangzhou, China
Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine,
Department of Cardiology, Afﬁliated Hospital of Qingdao University, Qingdao, China
Received: June 29, 2017; Accepted: October 6, 2017
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 phos-
phorylated mTOR and ribosomal protein S6 expression, but not Akt in both normal and aortic-banded mice. Moreover, chronic rapamycin treat-
ment 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
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
GSK3b, 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.
ischaemia reperfusion injury
Emerging evidence has demonstrated that left ventricular hypertrophy
(LVH) is an independent predictor of cardiovascular events  and
increases the risk of acute myocardial infarction (AMI) . LVH is
present in approximately one-third patients with AMI and is causally
related to increased morbidity and mortality following AMI . More-
over, experimental studies have shown that animals with LVH have
expanded myocardial infarct size and are refractory to
cardioprotective treatments due to defective cytoprotective mecha-
nisms following myocardial ischaemia–reperfusion (MI/R) [3, 4].
Therefore, it is urgent to develop novel therapeutic strategies to fur-
ther reduce infarct size, preserve cardiac function and improve the
outcome of AMI patients with LVH.
Cardiac hypertrophy is an important adaptive response to haemo-
dynamic overload, such as pressure overload . In response to
These authors contributed equally to this work.
*Correspondence to: Jun-Bo Ge
ª 2018 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
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J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1708-1719