Review Article
Aldehyde Dehydrogenase 2 in Cardiac Protection: A New Therapeutic Target?

https://doi.org/10.1016/j.tcm.2009.09.003Get rights and content

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 ɛ 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.

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

References (59)

  • LiuG.S. et al.

    Protein kinase C-epsilon is responsible for the protection of preconditioning in rabbit cardiomyocytes

    J Mol Cell Cardiol

    (1999)
  • MurrielC.L. et al.

    Protein kinase Cdelta activation induces apoptosis in response to cardiac ischemia and reperfusion damage: a mechanism involving BAD and the mitochondria

    J Biol Chem

    (2004)
  • NakamuraY. et al.

    Long-term nitrate use may be deleterious in ischemic heart disease: a study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group

    Am Heart J

    (1999)
  • PetersenD.R. et al.

    Reactions of 4-hydroxynonenal with proteins and cellular targets

    Free Radic Biol Med

    (2004)
  • SiemsW.G. et al.

    4-hydroxynonenal inhibits Na(+)-K(+)-ATPase

    Free Radic Biol Med

    (1996)
  • UchidaK. et al.

    Covalent attachment of 4-hydroxynonenal to glyceraldehyde-3-phosphate dehydrogenase. A possible involvement of intra- and intermolecular cross-linking reaction

    J Biol Chem

    (1993)
  • VasiliouV. et al.

    Role of aldehyde dehydrogenases in endogenous and xenobiotic metabolism

    Chem Biol Interact

    (2000)
  • ArmstrongS. et al.

    Preconditioning of isolated rabbit cardiomyocytes: induction by metabolic stress and blockade by the adenosine antagonist SPT and calphostin C, a protein kinase C inhibitor

    Cardiovasc Res

    (1994)
  • ArnoldW.P. et al.

    Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations

    Proc Natl Acad Sci U S A

    (1977)
  • BainesC.P. et al.

    Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria

    Circ Res

    (2003)
  • BainesC.P. et al.

    Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death

    Nature

    (2005)
  • BlasigI.E. et al.

    4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion injury of the myocardium

    Am J Physiol

    (1995)
  • BolliR.

    Preconditioning: a paradigm shift in the biology of myocardial ischemia

    Am J Physiol Heart Circ Physiol

    (2007)
  • BolliR. et al.

    Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog

    Proc Natl Acad Sci U S A

    (1989)
  • BrienJ.F. et al.

    Mechanism of glyceryl trinitrate-induced vasodilation. I. Relationship between drug biotransformation, tissue cyclic GMP elevation and relaxation of rabbit aorta

    J Pharmacol Exp Ther

    (1988)
  • ChenZ. et al.

    Identification of the enzymatic mechanism of nitroglycerin bioactivation

    Proc Natl Acad Sci U S A

    (2002)
  • ChenZ. et al.

    An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation

    Proc Natl Acad Sci U S A

    (2005)
  • ChenC.H. et al.

    Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart

    Science

    (2008)
  • ChurchillE.N. et al.

    Reperfusion-induced translocation of deltaPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation

    Circ Res

    (2005)
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    This work was supported by NIAA11147 to DMR and in part, by an American Heart Association postdoctoral fellowship to GRB.

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