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Doctoral Thesis
DOI
10.11606/T.42.2017.tde-07032017-100454
Document
Author
Full name
Vanessa Morais Lima
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2016
Supervisor
Committee
Ferreira, Julio Cesar Batista (President)
Akamine, Eliana Hiromi
Diniz, Gabriela Placoná
Lotufo, Paulo Andrade
Tanaka, Leonardo Yuji
Title in Portuguese
Papel da mutação ALDH2*2 na insuficiência cardíaca: potencial terapêutico da Alda-1.
Keywords in Portuguese
Alda-1
ALDH2
Insuficiência cardíaca
Metabolismo mitocondrial
Mutação ALDH2*2
Abstract in Portuguese
A enzima aldeído desidrogenase 2 (ALDH2), localizada na matriz mitocondrial, é crucial na manutenção do balanço intracelular de aldeídos. Atualmente, estima-se que 8% da população mundial apresentam uma mutação pontual no gene da ALDH2 (E487K, ALDH2*2) que confere perda de até 95% na atividade enzimática. No presente projeto utilizamos camundongos knock-in ALDH2*2 para avaliar o impacto da mutação ALDH2 (E487K) na disfunção cardíaca induzida pelo infarto do miocárdio. Observamos que os animais mutantes possuem a atividade da ALDH2 reduzida e desenvolvem disfunção cardíaca e remodelamento ventricular semelhante aos animais selvagens após infarto do miocárdio. Porém, os animais com a mutação E487K possuem uma significante redução no consumo de oxigênio basal (respirometria), máximo (teste físico até a exaustão) e em mitocôndria cardíaca isolada, quando comparados aos animais selvagens. Por fim, o tratamento sustentado com Alda-1 (ativador da ALDH2) foi efetivo em restaurar a função cardíaca dos animais infartados, independente do genótipo.
Title in English
Role of ALDH2*2 mutation in heart failure: therapeutic potencial of Alda-1.
Keywords in English
Alda-1
ALDH2
ALDH2*2 mutation
Heart failure
Mitochondrial metabolism
Abstract in English
Aldehyde dehydrogenase 2 (ALDH2), located in the mitochondrial matrix, is critical for the maintenance of cellular redox balance by removing reactive aldehydes produced during oxidative stress. It is estimated that 8% of the world population have a point mutation in the ALDH2 gene (E487K), which reduces its enzymatic activity by 95%. Here, we study the impact of the E487K variant of ALDH2 on myocardial infarction-induced heart failure, using ALDH2 E487K knock-in mice. We observed that mice carrying the ALDH2 variant have reduced ALDH2 activity and protein levels compared to WT mice. Despite of reduced oxidative metabolism, animals with ALDH2 mutation develop cardiac dysfunction and ventricular remodeling equivalent to WT animals after myocardial infarction. Finally, sustained Alda-1 treatment (ALDH2 activator) during 6 weeks improved cardiac function of infarcted animals, regardless of genotype.
 
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Release Date
2019-03-07
Publishing Date
2017-03-07
 
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