Review ArticleAldehyde Dehydrogenase 2 in Cardiac Protection: A New Therapeutic Target?☆
Introduction
Clinical interventions for acute myocardial infarction, such as angioplasty or thrombolysis, are aimed at disrupting the occlusion and restoring coronary flow. However, these treatments do not prevent myocardial tissue damage during ischemia, nor do they reduce reperfusion injury. Therefore, the identification of novel cardioprotective strategies remains a clinical priority. The mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) is rapidly emerging as a crucial enzyme involved in protecting the heart from ischemic injury (Chen et al., 2008, Churchill et al., 2009, Doser et al., 2009, Lagranha et al., 2009, Perlman et al., 2009). ALDH2 is one of 19 members of the ALDH gene family which play a crucial metabolic role in the oxidation and detoxification of reactive aldehydes in a range of organs and cell types (Vasiliou and Nebert 2005). Although probably best known for its role in catalyzing the oxidation of acetaldehyde to acetic acid in ethanol metabolism, ALDH2 is also a key metabolic enzyme involved in the detoxification of other reactive aldehydes such as 4-hydroxy-2-nonenal (4-HNE). In addition to its dehydrogenase activity, ALDH2 has an reductase activity that catalyses the conversion of nitroglycerin (glyceryl trinitrate [GTN]) to 1,2-glyceryl dinitrate (1,2-GDN) and, thus, mediates bioactivation of GTN (Chen and Stamler, 2006, Chen et al., 2005). ALDH2 is encoded in the nucleus and co-translationally imported into the mitochondrial matrix, owing to a 17-amino-acid N-terminal mitochondrial localization sequence (Vasiliou and Nebert 2005). A common human polymorphism in ALDH2, in which a glutamate at amino acid 487 is replaced by a lysine (E487K), has the highest prevalence (40%) in the Asian population (Goedde et al. 1983). The functional ALDH2 enzyme is a tetramer; therefore, if any of the four subunits contains the E487K form, the activity of the enzyme is severely compromised. Thus, relative to the wild-type homozygotes (ALDH2*1), E487/K487 heterozygotes (ALDH2*1/2) have 30-40% of the activity and K487 homozygotes (ALDH2*2/2) show negligible activity (Chen et al., 2008, Goedde et al., 1983). The ALDH2*2 carriers experience facial flushing after alcohol ingestion (due to impaired acetaldehyde oxidation) and have reduced vasodilation in response to GTN (due to impaired bioconversion of GTN) (Li et al., 2006, Mackenzie et al., 2005). In addition, carriers of the ALDH2*2 allele have increased susceptibility to certain cancers and neurodegenerative diseases (Vasiliou et al. 2000).
Our laboratory recently identified ALDH2 as a key mediator of endogenous cytoprotection against myocardial ischemia/reperfusion injury (Chen et al. 2008). We found an inverse correlation between ALDH2 activity and infarct size in a myocardial infarction model and, using a novel small molecule activator of ALDH2, confirmed that ALDH2 activation is sufficient to protect the heart from ischemic damage. In this review, we will suggest possible cardioprotective mechanisms mediated by ALDH2, and the potential clinical implications of these findings.
Section snippets
ALDH2 Phosphorylation and Activity Correlates with Cardioprotection
One of the most powerful methods of reducing myocardial infarct size is by “preconditioning” the heart with sub-lethal periods of ischemia and reperfusion before the onset of sustained ischemia (Murry et al. 1986). The observation that adenosine and other G-protein coupled receptor (GPCR) agonists can mimic ischemic preconditioning (IPC) and confer cardioprotection (Liu et al. 1991) led to the hypothesis that protein kinase C (PKC), which lies downstream from these Gi-coupled receptors, was
Summary
Accumulating evidence suggests that mitochondrial ALDH2 plays a pivotal role in mediating cytoprotective signaling in the heart. ALDH2 may confer cardioprotection through metabolism of reactive aldehydes (such as 4-HNE) and through its role in the bioconversion of nitrates to NO. Therefore, ALDH2 agonists, such as Alda-1, may ultimately lead to novel therapies which limit injury during myocardial infarction or bypass surgery. Because activation of ALDH2 is protective, agents that that impair
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2022, Phytomedicine PlusCitation Excerpt :Previous studies have confirmed that cardiac functions can be seriously impaired by excessive toxic aldehydes, such as 4‑hydroxy-2-nonenal (4-HNE) derived from ischemia/reperfusion (I/R) injury (Zhang et al., 2010). Aldehyde dehydrogenase-2 (ALDH2), a mitochondrial protein enzyme, is critically involved in the metabolism of acetaldehyde as well as other toxic aldehydes and exerts beneficial roles in reactive oxygen species (ROS) generation caused by toxic aldehydes, acetaldehyde and alcohol, tissue injury, and oxidative stress-induced cell apoptosis (Budas et al., 2009; Ma et al., 2011). Furthermore, previous studies have reported the cardioprotective functions of ALDH2 during cardiac I/R injury (Chen et al., 2008).
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2021, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Both the cell size and ROS production changed in parallel across experimental conditions, contrary to the observed with the SR Ca2+ release. Given that ROS availability is directly proportional to the activity of ALDH2 [4,5], the most plausible explanation for our findings is that the aldosterone signaling enhances SR Ca2+ release upstream of oxidative stress, and it is the latter that leads to hypertrophy. The results supporting this view are described in detail below, along with the possible pathophysiological implications of our study.
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This work was supported by NIAA11147 to DMR and in part, by an American Heart Association postdoctoral fellowship to GRB.