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Adenovirus (ADV) and adeno\u2010associated 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\u20108 kit and TUNEL staining. Mitochondrial function was determined by the mitochondrial membrane potential and oxygen consumption rates. AAV9\u2010HINT2 was injected 24\u00a0h post\u2010myocardial infarction following which transthoracic echocardiography and histological analyses were performed after 4\u00a0weeks. Positron emission tomography tomography\u2010computed 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\u2010simulated rigid body molecular docking was performed using AUTODOCK4. Molecule binding kinetics assays were performed using biolayer interferometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HINT2 was down\u2010regulated in NMVMs in hypoxia. ADV\u2010HINT2\u2010induced HINT2 overexpression improved NMVM survival after exposure to hypoxia. Mitochondrial function was preserved in the ADV\u2010HINT2 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\u2010simulated molecular docking analysis and biolayer interferometry, we observed that HINT2 potentially binds and associates with NMN.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>HINT2 overexpression protects cardiac function in adult mice after myocardial infarction by maintaining mitochondrial NAD homeostasis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13439","type":"journal-article","created":{"date-parts":[[2020,1,4]],"date-time":"2020-01-04T07:17:10Z","timestamp":1578122230000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Overexpression of the histidine triad nucleotide\u2010binding protein 2 protects cardiac function in the adult mice after acute myocardial 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