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Science 12 September 2008:
Vol. 321. no. 5895, pp. 1493 - 1495
DOI: 10.1126/science.1158554
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Reports

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

Che-Hong Chen,1 Grant R. Budas,1 Eric N. Churchill,1 Marie-Hélène Disatnik,1 Thomas D. Hurley,2 Daria Mochly-Rosen1*

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.

1 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305–5174, USA.
2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

* To whom correspondence should be addressed. E-mail: mochly{at}stanford.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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N. Engl. J. Med. 360, 532-534
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Science. ISSN 0036-8075 (print), 1095-9203 (online)