Aldehyde dehydrogenase 2 in cardiac protection: a new therapeutic target?

Abstract

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is emerging as a key enzyme involved in cytoprotection in the heart. ALDH2 mediates both the detoxification of reactive aldehydes such as acetaldehyde and 4-hydroxy-2-nonenal and the bioactivation of nitroglycerin to nitric oxide. In addition, chronic nitrate treatment results in ALDH2 inhibition and contributes to nitrate tolerance. Our laboratory recently identified ALDH2 to be a key mediator of endogenous cytoprotection. We reported that ALDH2 is phosphorylated and activated by the survival kinase protein kinase C epsilon and found a strong inverse correlation between ALDH2 activity and infarct size. We also identified a small molecule ALDH2 activator which reduces myocardial infarct size induced by ischemia/reperfusion in vivo. In this review, we discuss evidence that ALDH2 is a key mediator of endogenous survival signaling in the heart, suggest possible cardioprotective mechanisms mediated by ALDH2 and discuss potential clinical implications of these findings.

Figure 1. ALDH2 activity correlates with cardiac protection

A) ALDH2 activity correlates with cardiac protection. Activation of PKCε (with ethanol or ΨεRACK) increased ALDH2 activity and reduced infarct size. Conversely, PKCε-induced cardioprotection and the concomitant increase in ALDH2 activity were blocked when PKCε was inhibited with εV_1–2. When ALDH2 was inhibited (with cyanamide or nitroglycerin), infarct size was increased. Linear regression demonstrates a strong inverse correlation between infarct size and ALDH2 activity (R²=0.95). From Chen et al. Science (2008). Reprinted with permission from AAAS.

Figure 2. Scheme of PKCε mediated activation of ALDH2

On activation (with ethanol, preconditioning or ΨεRACK) PKCε translocates from the cytosol to the mitochondria and phosphorylates ALDH2, increasing enzymatic activity. PKCε-mediated activation of ALDH2 increases detoxification of reactive aldehydes, such as 4-HNE, a cytotoxic aldehyde that accumulates during cardiac ischemia injury as a by product of ROS-induced lipid peroxidation. Enhanced ALDH2 activity reduces 4-HNE protein adduct formation and increases cell survival.

Figure 3. Alda-1 activates wild-type and mutant ALDH2

A) Activation of wild-type and mutant ALDH2 by Alda-1. Enzymatic activity of recombinant ALDH2 proteins (20μg) in the absence and presence of 100μM Alda-1 (n=3 for each, **p<0.01 vs. control). From Chen et al. Science (2008). Reprinted with permission from AAAS.

Figure 4. Alda-1 prevents 4-HNE-induced inactivation of ALDH2

Treatment with 200μM 4-HNE results in inactivation of recombinant ALDH2 and is blocked by co-incubation with 20μM Alda-1. Thus, Alda-1 prevents 4-HNE-induced ALDH2 inactivation. From Chen et al. Science (2008). Reprinted with permission from AAAS.

Figure 5. Scheme of Alda-1 mediated cardioprotection

ALDH2 plays a pivotal role in cardioprotective signaling through its dual role in the bioactivation of GTN to nitric oxide-related species (NOx) and in the detoxification of reactive aldehydes (such as 4-HNE and acetaldehyde), to non-reactive acids (such as 4-HNA and acetic acid). Alda-1 treatment increases ALDH2 activity and also prevents inhibition of ALDH2 (by GTN or 4-HNE) and thus ensures continued detoxification of reactive aldehydes during ischemia-reperfusion or during chronic treatment with GTN.