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