Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aldehyde Dehydrogenase / antagonists & inhibitors
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Aldehyde Dehydrogenase / metabolism*
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Aldehyde Dehydrogenase, Mitochondrial
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Aldehydes / metabolism
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Amino Acid Sequence
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Animals
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Benzamides / pharmacology*
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Benzodioxoles / pharmacology*
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Cardiotonic Agents / pharmacology*
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Cyanamide / pharmacology
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Enzyme Activation
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Ethanol / pharmacology
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Ischemic Preconditioning, Myocardial
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Mitochondrial Proteins / agonists
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Mitochondrial Proteins / antagonists & inhibitors
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Mitochondrial Proteins / metabolism*
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Molecular Sequence Data
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Myocardial Infarction / enzymology
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Myocardial Infarction / pathology
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Myocardial Infarction / prevention & control*
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Myocardial Reperfusion Injury / enzymology*
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Myocardium / enzymology*
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Myocardium / pathology
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Nitroglycerin / pharmacology
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Phosphorylation
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Protein Kinase C-epsilon / metabolism
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Proteomics
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Rats
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Rats, Wistar
Substances
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Aldehydes
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Benzamides
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Benzodioxoles
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Cardiotonic Agents
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Mitochondrial Proteins
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N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
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Ethanol
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Cyanamide
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Aldehyde Dehydrogenase
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Aldehyde Dehydrogenase, Mitochondrial
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Aldh2 protein, rat
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Protein Kinase C-epsilon
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Nitroglycerin
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4-hydroxy-2-nonenal