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

Autor(es):Mostrar menos -

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Cardiovascular Research; v. 114, n. 7, p. 1006-1015, JUN 1 2018.
• Citações Web of Science: 10

Resumo

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)

• Processo FAPESP: 12/05765-2 - Contribuição da enzima aldeído desidrogenase 2 na progressão da insuficiência cardíaca
• Beneficiário: Julio Cesar Batista Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/20783-5 - Controle de qualidade de proteína na disfunção/atrofia muscular esquelética: papel do receptor ²2- adrenérgico
• Beneficiário: Julio Cesar Batista Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/11315-2 - Potencial terapêutico da ativação da aldeído desidrogenase 2 em modelo de sobrecarga pressórica cardíaca induzida por coartação da aorta: papel da mutação ALDH2*2
• Beneficiário: Cintia Bagne Ueta
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado