Acute Inhibition of Excessive Mitochondrial Fission After Myocardial Infarction Prevents Long-term Cardiac Dysfunction

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Arquivos
art_DOURADO_Acute_Inhibition_of_Excessive_Mitochondrial_Fission_After_Myocardial_2013.PDF (1.78 MB)
Citações na Scopus
249
Tipo de produção
article
Data de publicação
2013
DOI
Scopus
Web of Science
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY-BLACKWELL
Autores
DISATNIK, Marie-Helene
FERREIRA, Julio C. B.
CAMPOS, Juliane Cruz
GOMES, Katia Sampaio
QI, Xin
MOCHLY-ROSEN, Daria
Citação
JOURNAL OF THE AMERICAN HEART ASSOCIATION, v.2, n.5, article ID e000461, 14p, 2013
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Background-Ischemia and reperfusion (IR) injury remains a major cause of morbidity and mortality and multiple molecular and cellular pathways have been implicated in this injury. We determined whether acute inhibition of excessive mitochondrial fission at the onset of reperfusion improves mitochondrial dysfunction and cardiac contractility postmyocardial infarction in rats. Methods and Results-We used a selective inhibitor of the fission machinery, P110, which we have recently designed. P110 treatment inhibited the interaction of fission proteins Fis1/Drp1, decreased mitochondrial fission, and improved bioenergetics in three different rat models of IR, including primary cardiomyocytes, ex vivo heart model, and an in vivo myocardial infarction model. Drp1 transiently bound to the mitochondria following IR injury and P110 treatment blocked this Drp1 mitochondrial association. Compared with control treatment, P110 (1 mu mol/L) decreased infarct size by 28 +/- 2% and increased adenosine triphosphate levels by 70+1% after IR relative to control IR in the ex vivo model. Intraperitoneal injection of P110 (0.5 mg/kg) at the onset of reperfusion in an in vivo model resulted in improved mitochondrial oxygen consumption by 68% when measured 3 weeks after ischemic injury, improved cardiac fractional shortening by 35%, reduced mitochondrial H2O2 uncoupling state by 70%, and improved overall mitochondrial functions. Conclusions-Together, we show that excessive mitochondrial fission at reperfusion contributes to long-term cardiac dysfunction in rats and that acute inhibition of excessive mitochondrial fission at the onset of reperfusion is sufficient to result in long-term benefits as evidenced by inhibiting cardiac dysfunction 3 weeks after acute myocardial infarction.
Palavras-chave
cardiac myocytes, Drp1, heart, mitochondria, protein-protein interaction inhibitor
URI
https://observatorio.fm.usp.br/handle/OPI/4537
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Coleções
Artigos e Materiais de Revistas Científicas - HC/InCor
Artigos e Materiais de Revistas Científicas - ODS/03