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 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.
Chen
Che-Hong
CH
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA.
Budas
Grant R
GR
Churchill
Eric N
EN
Disatnik
Marie-Hélène
MH
Hurley
Thomas D
TD
Mochly-Rosen
Daria
D
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003484:Cyanamide / Q000494:pharmacology; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D024101:Mitochondrial Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D005996:Nitroglycerin / Q000494:pharmacology; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D040901:Proteomics; D051381:Rats; D017208:Rats, Wistar
D000447:Aldehydes; D001549:Benzamides; D052117:Benzodioxoles; D002316:Cardiotonic Agents; D024101:Mitochondrial Proteins; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D000431:Ethanol; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D051744:Protein Kinase C-epsilon; D005996:Nitroglycerin; C027576:4-hydroxy-2-nonenal
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