Abstract 3879: Activation of Aldehyde Dehydrogenase 2 Confers Cardioprotection In Protein Kinase C Epsilon Knockout Mice
We previously demonstrated that acute ethanol administration can protect the intact heart and isolated cardiomyocytes from ischemic injury. We subsequently found that the direct cardioprotective effect of ethanol on the myocardium requires activation of the epsilon isozyme of protein kinase C (ϵPKC) and is abolished by the ϵPKC-selective inhibitor ϵV1–2. Proteomic analysis identified aldehyde dehydrogenase 2 (ALDH2) as an ϵPKC substrate, whose activity strongly correlates with cardioprotection. ALDH2 is a mitochondrial enzyme and is part of the ethanol metabolic pathway, converting acetaldehyde (produced by alcohol dehydrogenase) to acetic acid. ALDH2 also detoxifies other aromatic and aliphatic aldehydes, such as 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA) which are reactive by-products of lipid peroxidation. ALDH2-mediated detoxification of reactive aldehydes, which accumulate in the ischemic heart, is therefore a possible cardioprotective mechanism. In order to further investigate the interplay between ϵPKC and ALDH2 in mediating the cardioprotective effect of ethanol, we used a combination of ϵPKC knockout mice and a direct activator of ALDH2. Using an ex vivo murine model of IR injury (35 minutes of ischemia followed by 60 minutes of reperfusion), we found that 50mM ethanol pretreatment (20 minutes perfusion followed by 5 minutes washout prior to ischemia onset) could reduce IR injury, measured as infarct size and creatine kinase release, in wild-type but not in ϵPKC knockout mice. This finding was in agreement with previous observations that the cardioprotective effect of ethanol requires ϵPKC and that ϵPKC deficient mouse hearts are resistant to ischemic preconditioning. Interestingly, direct activation of ALDH2 significantly increased the enzymatic activity of ALDH2, reduced accumulation of 4-HNE protein adducts and reduced necrotic cell death induced by IR in both wild type and ϵPKC knockout hearts. The observation that direct activation of ALDH2 is sufficient to confer cardioprotection in the absence of ϵPKC suggests that ALDH2 is downstream of ϵPKC in the signaling of ethanol preconditioning. ALDH2 is therefore a promising therapeutic target in the treatment of predictable myocardial ischemia.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).