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

Author(s):Show less -

Ueta, Cintia Bagne ^[1] ; Campos, Juliane Cruz ^[1] ; Prestes e Albuquerque, Ruda ^[1] ; Lima, Vanessa Morais ^[1] ; Disatnik, Marie-Helene ^[2] ; Sanchez, Angelica Bianchini ^[3] ; Chen, Che-Hong ^[2] ; Gennari de Medeiros, Marisa Helena ^[3] ; Yang, Wenjin ^[4] ; Mochly-Rosen, Daria ^[2] ; Batista Ferreira, Julio Cesar ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Prof Lineu Prestes 2415, BR-05508000 Sao Paulo, SP - Brazil

^[2] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 - USA

^[3] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo - Brazil

^[4] Foresee Pharmaceut Co Ltd, Taipei - Taiwan

• Document type: Journal article
• Source: Cardiovascular Research; v. 114, n. 7, p. 1006-1015, JUN 1 2018.
• Web of Science Citations: 2

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 mu M 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 threefold 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. (AU)

• FAPESP's process: 13/11315-2 - Therapeutic potential of the aldehyde dehydrogenase 2 activation in a model of aortic coarctation-induced pressure overload: role of ALDH2*2 mutation
• Grantee: Cintia Bagne Ueta
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 12/05765-2 - Contribution of aldehyde dehydrogenase 2 to heart failure development
• Grantee: Julio Cesar Batista Ferreira
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 15/20783-5 - Protein quality control in dysfunctional/atrophic skeletal muscle: role of b2-adrenoceptor
• Grantee: Julio Cesar Batista Ferreira
• Support type: Regular Research Grants