Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2

• Published in: Cardiovascular research 2018-06, Vol.114 (7), p.1006-1015
• Main Authors: Ueta, Cintia Bagne, Campos, Juliane Cruz, Albuquerque, Rudá Prestes e, Lima, Vanessa Morais, Disatnik, Marie-Hélène, Sanchez, Angélica Bianchini, Chen, Che-Hong, de Medeiros, Marisa Helena Gennari, Yang, Wenjin, Mochly-Rosen, Daria, Ferreira, Julio Cesar Batista
• Format: Article
• Language: English
• Subjects: Acetaldehyde - metabolism; Acetaldehyde - pharmacology; Acetaldehyde - toxicity; Aldehyde Dehydrogenase, Mitochondrial - genetics; Aldehyde Dehydrogenase, Mitochondrial - metabolism; Animals; Cardiotoxicity; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Gene Knock-In Techniques; Genotype; Humans; Male; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction - enzymology; Myocardial Infarction - genetics; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Original; Phenotype; Point Mutation; Rats; Time Factors
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvy070

Abstract Aims We previously demonstrated that acute ethanol administration protects the heart from ischaemia/reperfusion (I/R) injury thorough activation of aldehyde dehydrogenase 2 (ALDH2). Here, we characterized the role of acetaldehyde, an intermediate product from ethanol metabolism, and its metabolizing enzyme, ALDH2, in an ex vivo model of cardiac I/R injury. Methods and results We used a combination of homozygous knock-in mice (ALDH2*2), carrying the human inactivating point mutation ALDH2 (E487K), and a direct activator of ALDH2, Alda-1, to investigate the cardiac effect of acetaldehyde. The ALDH2*2 mice have impaired acetaldehyde clearance, recapitulating the human phenotype. Yet, we found a similar infarct size in wild type (WT) and ALDH2*2 mice. Similar to ethanol-induced preconditioning, pre-treatment with 50 μM acetaldehyde increased ALDH2 activity and reduced cardiac injury in hearts of WT mice without affecting cardiac acetaldehyde levels. However, acetaldehyde pre-treatment of hearts of ALDH2*2 mice resulted in a three-fold increase in cardiac acetaldehyde levels and exacerbated I/R injury. Therefore, exogenous acetaldehyde appears to have a bimodal effect in I/R, depending on the ALDH2 genotype. Further supporting an ALDH2 role in cardiac preconditioning, pharmacological ALDH2 inhibition abolished ethanol-induced cardioprotection in hearts of WT mice, whereas a selective activator, Alda-1, protected ALDH2*2 against ethanol-induced cardiotoxicity. Finally, either genetic or pharmacological inhibition of ALDH2 mitigated ischaemic preconditioning. Conclusion Taken together, our findings suggest that low levels of acetaldehyde are cardioprotective whereas high levels are damaging in an ex vivo model of I/R injury and that ALDH2 is a major, but not the only, regulator of cardiac acetaldehyde levels and protection from I/R.