Open AccessMammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart
Author(s) -
Ma LeiLei,
Ma Xin,
Kong FeiJuan,
Guo JunJie,
Shi HongTao,
Zhu JianBing,
Zou YunZeng,
Ge JunBo
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13451
Subject(s) - pi3k/akt/mtor pathway , autophagy , protein kinase b , reperfusion injury , oxidative stress , ribosomal protein s6 , phosphorylation , mapk/erk pathway , medicine , pharmacology , endocrinology , biology , chemistry , microbiology and biotechnology , apoptosis , ischemia , signal transduction , biochemistry , p70 s6 kinase 1
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 LC 3‐ II / LC 3‐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 GSK 3β, 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.