Overexpression of the histidine triad nucleotide-binding protein 2 protects cardiac function in the adult mice after acute myocardial infarction.
Acta Physiol (Oxf)
; 228(4): e13439, 2020 04.
Article
em En
| MEDLINE
| ID: mdl-31900976
ABSTRACT
AIM:
To explore the role of the histidine triad nucleotide-binding 2 (HINT2) protein in heart failure.METHODS:
Neonatal mouse ventricle myocytes (NMVMs) and myocardial infarction-induced heart failure mice were used for in vitro or in vivo experiments. Adenovirus (ADV) and adeno-associated virus serum type 9 (AAV9) vectors were used to regulate HINT2 expression. The expression of HINT2 was determined by quantifying the mRNA and protein levels. Cell survival was analysed using the CCK-8 kit and TUNEL staining. Mitochondrial function was determined by the mitochondrial membrane potential and oxygen consumption rates. AAV9-HINT2 was injected 24 h post-myocardial infarction following which transthoracic echocardiography and histological analyses were performed after 4 weeks. Positron emission tomography tomography-computed tomography (PET/CT) and targeted metabolomics analyses were used to explore the metabolic status in vivo. NAD levels were measured using a colorimetric kit. Computer-simulated rigid body molecular docking was performed using AUTODOCK4. Molecule binding kinetics assays were performed using biolayer interferometry.RESULTS:
HINT2 was down-regulated in NMVMs in hypoxia. ADV-HINT2-induced HINT2 overexpression improved NMVM survival after exposure to hypoxia. Mitochondrial function was preserved in the ADV-HINT2 group under hypoxic conditions. In vivo experiments showed that cardiac function and metabolic status was preserved by HINT2 overexpression. HINT2 overexpression restored mitochondrial NAD levels; this was dependent on nicotinamide mononucleotide (NMN). Using computer-simulated molecular docking analysis and biolayer interferometry, we observed that HINT2 potentially binds and associates with NMN.CONCLUSION:
HINT2 overexpression protects cardiac function in adult mice after myocardial infarction by maintaining mitochondrial NAD homeostasis.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Mitocondriais
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Coração
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Hidrolases
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Infarto do Miocárdio
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article