Activation of Aldehyde Dehydrogenase-2 Reduces Ischemic Damage to the Heart

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 wh...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2008-09, Vol.321 (5895), p.1493-1495
Main Authors: Chen, Che-Hong, Budas, Grant R, Churchill, Eric N, Disatnik, Marie-Hélène, Hurley, Thomas D, Mochly-Rosen, Daria
Format: Article
Language:English
Subjects:
Agonists
Aldehyde Dehydrogenase - antagonists & inhibitors
Aldehyde Dehydrogenase - metabolism
Aldehyde Dehydrogenase, Mitochondrial
Aldehydes
Aldehydes - metabolism
Amino Acid Sequence
Animals
Antianginal agents. Coronary vasodilator agents
Benzamides - pharmacology
Benzodioxoles - pharmacology
Biochemistry
Biological and medical sciences
Cardiology
Cardiology. Vascular system
Cardiotonic Agents - pharmacology
Cardiovascular system
Coronary heart disease
Cyanamide - pharmacology
Dehydrogenases
Enzyme Activation
Enzymes
Ethanol
Ethanol - pharmacology
Heart
Heart attacks
Ischemia
Ischemic Preconditioning, Myocardial
Medical sciences
Mitochondrial Proteins - agonists
Mitochondrial Proteins - antagonists & inhibitors
Mitochondrial Proteins - metabolism
Molecular Sequence Data
Myocardial infarction
Myocardial Infarction - enzymology
Myocardial Infarction - pathology
Myocardial Infarction - prevention & control
Myocardial reperfusion
Myocardial Reperfusion Injury - enzymology
Myocardium - enzymology
Myocardium - pathology
Nitroglycerin - pharmacology
Pharmacology
Pharmacology. Drug treatments
Phosphorylation
Protein Kinase C-epsilon - metabolism
Proteomics
Rats
Rats, Wistar
Rodents
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1158554