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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2014
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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. |
format | Online Article Text |
id | pubmed-4323818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
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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