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Activation of Aldehyde Dehydrogenase-2 Reduces Ischemic Damage to the Heart
Che-Hong Chen,1Grant R. Budas,1Eric N. Churchill,1Marie-Hélène Disatnik,1Thomas D. Hurley,2Daria Mochly-Rosen1*
There is substantial interest in the development of drugs thatlimit the extent of ischemia-induced cardiac damage caused bymyocardial infarction or by certain surgical procedures. Here,using an unbiased proteomic search, we identified mitochondrialaldehyde dehydrogenase 2 (ALDH2) as an enzyme whose activationcorrelates with reduced ischemic heart damage in rodent models.A high-throughput screen yielded a small-molecule activatorof ALDH2 (Alda-1) that, when administered to rats before anischemic event, reduced infarct size by 60%, most likely throughits 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% ofEast Asian populations. Thus, pharmacologic enhancement of ALDH2activity may be useful for patients with wild-type or mutantALDH2 who are subjected to cardiac ischemia, such as duringcoronary 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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