Document Detail


Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart.
MedLine Citation:
PMID:  18787169     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
There is substantial interest in the development of drugs that limit the extent of ischemia-induced cardiac damage caused by myocardial infarction or by certain surgical procedures. Here, using an unbiased proteomic search, we identified mitochondrial aldehyde dehydrogenase 2 (ALDH2) as an enzyme whose activation correlates with reduced ischemic heart damage in rodent models. A high-throughput screen yielded a small-molecule activator of ALDH2 (Alda-1) that, when administered to rats before an ischemic event, reduced infarct size by 60%, most likely through its inhibitory effect on the formation of cytotoxic aldehydes. In vitro, Alda-1 was a particularly effective activator of ALDH2*2, an inactive mutant form of the enzyme that is found in 40% of East Asian populations. Thus, pharmacologic enhancement of ALDH2 activity may be useful for patients with wild-type or mutant ALDH2 who are subjected to cardiac ischemia, such as during coronary bypass surgery.
Authors:
Che-Hong Chen; Grant R Budas; Eric N Churchill; Marie-Hélène Disatnik; Thomas D Hurley; Daria Mochly-Rosen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Science (New York, N.Y.)     Volume:  321     ISSN:  1095-9203     ISO Abbreviation:  Science     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-09-12     Completed Date:  2008-09-25     Revised Date:  2014-09-09    
Medline Journal Info:
Nlm Unique ID:  0404511     Medline TA:  Science     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1493-5     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Dehydrogenase / antagonists & inhibitors,  metabolism*
Aldehydes / metabolism
Amino Acid Sequence
Animals
Benzamides / pharmacology*
Benzodioxoles / pharmacology*
Cardiotonic Agents / pharmacology*
Cyanamide / pharmacology
Enzyme Activation
Ethanol / pharmacology
Ischemic Preconditioning, Myocardial
Mitochondrial Proteins / agonists,  antagonists & inhibitors,  metabolism*
Molecular Sequence Data
Myocardial Infarction / enzymology,  pathology,  prevention & control*
Myocardial Reperfusion Injury / enzymology*
Myocardium / enzymology*,  pathology
Nitroglycerin / pharmacology
Phosphorylation
Protein Kinase C-epsilon / metabolism
Proteomics
Rats
Rats, Wistar
Grant Support
ID/Acronym/Agency:
AA11147/AA/NIAAA NIH HHS; R01 AA011147/AA/NIAAA NIH HHS; R01 AA011147-08/AA/NIAAA NIH HHS; R01 AA011147-09/AA/NIAAA NIH HHS; R01 AA011147-10/AA/NIAAA NIH HHS; R01 AA011147-11/AA/NIAAA NIH HHS; R01 AA011147-12/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/Aldehydes; 0/Benzamides; 0/Benzodioxoles; 0/Cardiotonic Agents; 0/Mitochondrial Proteins; 0/N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; 29343-52-0/4-hydroxy-2-nonenal; 3K9958V90M/Ethanol; 420-04-2/Cyanamide; EC 1.2.1.3/Aldehyde Dehydrogenase; EC 1.2.1.3/Aldh2 protein, rat; EC 2.7.11.13/Protein Kinase C-epsilon; G59M7S0WS3/Nitroglycerin
Comments/Corrections

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