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Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice

BACKGROUND: Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined. METHODS AND RESULTS: Proteomic analysis identified a significant downreg...

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Autores principales: Sun, Aijun, Zou, Yunzeng, Wang, Ping, Xu, Danling, Gong, Hui, Wang, Shijun, Qin, Yingjie, Zhang, Peng, Chen, Yunqin, Harada, Mutsuo, Isse, Toyoshi, Kawamoto, Toshihiro, Fan, Huizhi, Yang, Pengyuan, Akazawa, Hiroshi, Nagai, Toshio, Takano, Hiroyuki, Ping, Peipei, Komuro, Issei, Ge, Junbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323818/
https://www.ncbi.nlm.nih.gov/pubmed/25237043
http://dx.doi.org/10.1161/JAHA.113.000779
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author Sun, Aijun
Zou, Yunzeng
Wang, Ping
Xu, Danling
Gong, Hui
Wang, Shijun
Qin, Yingjie
Zhang, Peng
Chen, Yunqin
Harada, Mutsuo
Isse, Toyoshi
Kawamoto, Toshihiro
Fan, Huizhi
Yang, Pengyuan
Akazawa, Hiroshi
Nagai, Toshio
Takano, Hiroyuki
Ping, Peipei
Komuro, Issei
Ge, Junbo
author_facet Sun, Aijun
Zou, Yunzeng
Wang, Ping
Xu, Danling
Gong, Hui
Wang, Shijun
Qin, Yingjie
Zhang, Peng
Chen, Yunqin
Harada, Mutsuo
Isse, Toyoshi
Kawamoto, Toshihiro
Fan, Huizhi
Yang, Pengyuan
Akazawa, Hiroshi
Nagai, Toshio
Takano, Hiroyuki
Ping, Peipei
Komuro, Issei
Ge, Junbo
author_sort Sun, Aijun
collection PubMed
description BACKGROUND: Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined. METHODS AND RESULTS: Proteomic analysis identified a significant downregulation of mitochondrial ALDH2 in the heart of a rat heart failure model after myocardial infarction. The mechanistic insights underlying ALDH2 action were elucidated using murine models overexpressing ALDH2 or its mutant or with the ablation of the ALDH2 gene (ALDH2 knockout) and neonatal cardiomyocytes undergoing altered expression and activity of ALDH2. Left ventricle dilation and dysfunction and cardiomyocyte death after myocardial infarction were exacerbated in ALDH2‐knockout or ALDH2 mutant‐overexpressing mice but were significantly attenuated in ALDH2‐overexpressing mice. Using an anoxia model of cardiomyocytes with deficiency in ALDH2 activities, we observed prominent cardiomyocyte apoptosis and increased accumulation of the reactive aldehyde 4‐hydroxy‐2‐nonenal (4‐HNE). We subsequently examined the impacts of mitochondrial ALDH2 and 4‐HNE on the relevant cytosolic protective pathways. Our data documented 4‐HNE‐stimulated p53 upregulation via the phosphorylation of JNK, accompanying increased cardiomyocyte apoptosis that was attenuated by inhibition of p53. Importantly, elevation of 4‐HNE also triggered a reduction of the cytosolic HSP70, further corroborating cytosolic action of the 4‐HNE instigated by downregulation of mitochondrial ALDH2. CONCLUSIONS: Downregulation of ALDH2 in the mitochondria induced an elevation of 4‐HNE, leading to cardiomyocyte apoptosis by subsequent inhibition of HSP70, phosphorylation of JNK, and activation of p53. This chain of molecular events took place in both the mitochondria and the cytosol, contributing to the mechanism underlying heart failure.
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spelling pubmed-43238182015-02-23 Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice Sun, Aijun Zou, Yunzeng Wang, Ping Xu, Danling Gong, Hui Wang, Shijun Qin, Yingjie Zhang, Peng Chen, Yunqin Harada, Mutsuo Isse, Toyoshi Kawamoto, Toshihiro Fan, Huizhi Yang, Pengyuan Akazawa, Hiroshi Nagai, Toshio Takano, Hiroyuki Ping, Peipei Komuro, Issei Ge, Junbo J Am Heart Assoc Original Research BACKGROUND: Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined. METHODS AND RESULTS: Proteomic analysis identified a significant downregulation of mitochondrial ALDH2 in the heart of a rat heart failure model after myocardial infarction. The mechanistic insights underlying ALDH2 action were elucidated using murine models overexpressing ALDH2 or its mutant or with the ablation of the ALDH2 gene (ALDH2 knockout) and neonatal cardiomyocytes undergoing altered expression and activity of ALDH2. Left ventricle dilation and dysfunction and cardiomyocyte death after myocardial infarction were exacerbated in ALDH2‐knockout or ALDH2 mutant‐overexpressing mice but were significantly attenuated in ALDH2‐overexpressing mice. Using an anoxia model of cardiomyocytes with deficiency in ALDH2 activities, we observed prominent cardiomyocyte apoptosis and increased accumulation of the reactive aldehyde 4‐hydroxy‐2‐nonenal (4‐HNE). We subsequently examined the impacts of mitochondrial ALDH2 and 4‐HNE on the relevant cytosolic protective pathways. Our data documented 4‐HNE‐stimulated p53 upregulation via the phosphorylation of JNK, accompanying increased cardiomyocyte apoptosis that was attenuated by inhibition of p53. Importantly, elevation of 4‐HNE also triggered a reduction of the cytosolic HSP70, further corroborating cytosolic action of the 4‐HNE instigated by downregulation of mitochondrial ALDH2. CONCLUSIONS: Downregulation of ALDH2 in the mitochondria induced an elevation of 4‐HNE, leading to cardiomyocyte apoptosis by subsequent inhibition of HSP70, phosphorylation of JNK, and activation of p53. This chain of molecular events took place in both the mitochondria and the cytosol, contributing to the mechanism underlying heart failure. Blackwell Publishing Ltd 2014-09-18 /pmc/articles/PMC4323818/ /pubmed/25237043 http://dx.doi.org/10.1161/JAHA.113.000779 Text en © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/3.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Sun, Aijun
Zou, Yunzeng
Wang, Ping
Xu, Danling
Gong, Hui
Wang, Shijun
Qin, Yingjie
Zhang, Peng
Chen, Yunqin
Harada, Mutsuo
Isse, Toyoshi
Kawamoto, Toshihiro
Fan, Huizhi
Yang, Pengyuan
Akazawa, Hiroshi
Nagai, Toshio
Takano, Hiroyuki
Ping, Peipei
Komuro, Issei
Ge, Junbo
Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice
title Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice
title_full Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice
title_fullStr Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice
title_full_unstemmed Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice
title_short Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice
title_sort mitochondrial aldehyde dehydrogenase 2 plays protective roles in heart failure after myocardial infarction via suppression of the cytosolic jnk/p53 pathway in mice
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323818/
https://www.ncbi.nlm.nih.gov/pubmed/25237043
http://dx.doi.org/10.1161/JAHA.113.000779
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