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.