Journal Article

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

Hurley, Thomas D, Churchill, Eric N, Mochly-Rosen, Daria, Chen, Che-Hong, Budas, Grant R, Disatnik, Marie-Hélène

2008

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Agonists / aldehyde dehydrogenase / Aldehyde Dehydrogenase - antagonists & inhibitors / Aldehyde Dehydrogenase - metabolism / Aldehyde Dehydrogenase, Mitochondrial / Aldehydes / Aldehydes - metabolism / Amino Acid Sequence / animal models / 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 / cytotoxicity / Dehydrogenase / Dehydrogenases / drugs / Enzyme Activation / Enzymes / Ethanol / Ethanol - pharmacology / Heart / Heart attacks / infarction / Ischemia / Ischemic Preconditioning, Myocardial / Medical sciences / mitochondria / Mitochondrial Proteins - agonists / Mitochondrial Proteins - antagonists & inhibitors / Mitochondrial Proteins - metabolism / Molecular Sequence Data / mutants / Myocardial infarction / Myocardial Infarction - enzymology / Myocardial Infarction - pathology / Myocardial Infarction - prevention & control / Myocardial reperfusion / Myocardial Reperfusion Injury - enzymology / Myocardium - enzymology / Myocardium - pathology / Nitroglycerin - pharmacology / patients / Pharmacology / Pharmacology. Drug treatments / Phosphorylation / Protein Kinase C-epsilon - metabolism / Proteomics / Rats / Rats, Wistar / Rodents / surgery