Journal
CARDIOVASCULAR RESEARCH
Volume 114, Issue 7, Pages 1006-1015Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvy070
Keywords
Ischaemia-reperfusion injury; Alcohol consumption; Mitochondria; Heart attack; Cardiovascular disease
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP 2012/05765-2, 2013/07937-8, 2015/20783-5]
- Conselho Nacional de Pesquisa e Desenvolvimento, Brasil [CNPq 303281/2015-4, 470880/2012-0, 407306/2013-7]
- National Institutes of Health [NIAAA R37 AA011147]
- FAPESP [2013/11315-2]
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA011147, R37AA011147] Funding Source: NIH RePORTER
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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.
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