Acute administration of
ethanol can reduce cardiac
ischemia/reperfusion injury. Previous studies demonstrated that the acute cytoprotective effect of
ethanol on the myocardium is mediated by
protein kinase C epsilon (PKCvarepsilon). We recently identified
aldehyde dehydrogenase 2 (ALDH2) as a PKCvarepsilon substrate, whose activation is necessary and sufficient to confer cardioprotection in vivo. ALDH2 metabolizes cytotoxic reactive
aldehydes, such as
4-hydroxy-2-nonenal (4-HNE), which accumulate during cardiac
ischemia/reperfusion. Here, we used a combination of PKCvarepsilon knockout mice and a direct activator of ALDH2, Alda-44, to further investigate the interplay between PKCvarepsilon and ALDH2 in cardioprotection. We report that
ethanol preconditioning requires PKCvarepsilon, whereas direct activation of ALDH2 reduces
infarct size in both wild type and PKCvarepsilon knockout hearts. Our data suggest that ALDH2 is downstream of PKCvarepsilon in
ethanol preconditioning and that direct activation of ALDH2 can circumvent the requirement of PKCvarepsilon to induce cytoprotection. We also report that in addition to ALDH2 activation, Alda-44 prevents 4-HNE induced inactivation of ALDH2 by reducing the formation of 4-HNE-ALDH2
protein adducts. Thus, Alda-44 promotes metabolism of cytotoxic reactive
aldehydes that accumulate in ischemic myocardium. Taken together, our findings suggest that direct activation of ALDH2 may represent a method of harnessing the cardioprotective effect of
ethanol without the side effects associated with alcohol consumption.