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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Autor(es):
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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]
Número total de Autores: 11
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
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: Cardiovascular Research; v. 114, n. 7, p. 1006-1015, JUN 1 2018.
Citações Web of Science: 5
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: 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
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 13/07937-8 - Redoxoma
Beneficiário:Ohara Augusto
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 12/05765-2 - Contribuição da enzima aldeído desidrogenase 2 na progressão da insuficiência cardíaca
Beneficiário:Julio Cesar Batista Ferreira
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
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
Linha de fomento: Auxílio à Pesquisa - Regular