Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart

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

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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.

Original languageEnglish (US)
Pages (from-to)1493-1495
Number of pages3
JournalScience
Volume321
Issue number5895
DOIs
StatePublished - Sep 12 2008

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Chen, C. H., Budas, G. R., Churchill, E. N., Disatnik, M. H., Hurley, T. D., & Mochly-Rosen, D. (2008). Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science, 321(5895), 1493-1495. https://doi.org/10.1126/science.1158554