Document Detail

Mitochondrial Aldehyde Dehydrogenase 2 Plays Protective Roles in Heart Failure After Myocardial Infarction via Suppression of the Cytosolic JNK/p53 Pathway in Mice.
MedLine Citation:
PMID:  25237043     Owner:  NLM     Status:  In-Data-Review    
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.
Aijun Sun; Yunzeng Zou; Ping Wang; Danling Xu; Hui Gong; Shijun Wang; Yingjie Qin; Peng Zhang; Yunqin Chen; Mutsuo Harada; Toyoshi Isse; Toshihiro Kawamoto; Huizhi Fan; Pengyuan Yang; Hiroshi Akazawa; Toshio Nagai; Hiroyuki Takano; Peipei Ping; Issei Komuro; Junbo Ge
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Publication Detail:
Type:  Journal Article     Date:  2014-09-18
Journal Detail:
Title:  Journal of the American Heart Association     Volume:  3     ISSN:  2047-9980     ISO Abbreviation:  J Am Heart Assoc     Publication Date:  2014  
Date Detail:
Created Date:  2014-09-19     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101580524     Medline TA:  J Am Heart Assoc     Country:  England    
Other Details:
Languages:  eng     Pagination:  -     Citation Subset:  IM    
Copyright Information:
© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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