Cargando…

Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart

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/ni...

Descripción completa

Detalles Bibliográficos
Autores principales: Ma, Lei‐Lei, Ma, Xin, Kong, Fei‐Juan, Guo, Jun‐Jie, Shi, Hong‐Tao, Zhu, Jian‐Bing, Zou, Yun‐Zeng, Ge, Jun‐Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824378/
https://www.ncbi.nlm.nih.gov/pubmed/29314656
http://dx.doi.org/10.1111/jcmm.13451
_version_ 1783302012253765632
author Ma, Lei‐Lei
Ma, Xin
Kong, Fei‐Juan
Guo, Jun‐Jie
Shi, Hong‐Tao
Zhu, Jian‐Bing
Zou, Yun‐Zeng
Ge, Jun‐Bo
author_facet Ma, Lei‐Lei
Ma, Xin
Kong, Fei‐Juan
Guo, Jun‐Jie
Shi, Hong‐Tao
Zhu, Jian‐Bing
Zou, Yun‐Zeng
Ge, Jun‐Bo
author_sort Ma, Lei‐Lei
collection PubMed
description 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 GSK3β, 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.
format Online
Article
Text
id pubmed-5824378
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-58243782018-03-01 Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart Ma, Lei‐Lei Ma, Xin Kong, Fei‐Juan Guo, Jun‐Jie Shi, Hong‐Tao Zhu, Jian‐Bing Zou, Yun‐Zeng Ge, Jun‐Bo J Cell Mol Med Original Articles 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 GSK3β, 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. John Wiley and Sons Inc. 2018-01-04 2018-03 /pmc/articles/PMC5824378/ /pubmed/29314656 http://dx.doi.org/10.1111/jcmm.13451 Text en © 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 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Ma, Lei‐Lei
Ma, Xin
Kong, Fei‐Juan
Guo, Jun‐Jie
Shi, Hong‐Tao
Zhu, Jian‐Bing
Zou, Yun‐Zeng
Ge, Jun‐Bo
Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart
title Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart
title_full Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart
title_fullStr Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart
title_full_unstemmed Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart
title_short Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart
title_sort mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824378/
https://www.ncbi.nlm.nih.gov/pubmed/29314656
http://dx.doi.org/10.1111/jcmm.13451
work_keys_str_mv AT maleilei mammaliantargetofrapamycininhibitionattenuatesmyocardialischaemiareperfusioninjuryinhypertrophicheart
AT maxin mammaliantargetofrapamycininhibitionattenuatesmyocardialischaemiareperfusioninjuryinhypertrophicheart
AT kongfeijuan mammaliantargetofrapamycininhibitionattenuatesmyocardialischaemiareperfusioninjuryinhypertrophicheart
AT guojunjie mammaliantargetofrapamycininhibitionattenuatesmyocardialischaemiareperfusioninjuryinhypertrophicheart
AT shihongtao mammaliantargetofrapamycininhibitionattenuatesmyocardialischaemiareperfusioninjuryinhypertrophicheart
AT zhujianbing mammaliantargetofrapamycininhibitionattenuatesmyocardialischaemiareperfusioninjuryinhypertrophicheart
AT zouyunzeng mammaliantargetofrapamycininhibitionattenuatesmyocardialischaemiareperfusioninjuryinhypertrophicheart
AT gejunbo mammaliantargetofrapamycininhibitionattenuatesmyocardialischaemiareperfusioninjuryinhypertrophicheart