PMID- 31900976 OWN - NLM STAT- MEDLINE DCOM- 20210602 LR - 20210602 IS - 1748-1716 (Electronic) IS - 1748-1708 (Linking) VI - 228 IP - 4 DP - 2020 Apr TI - Overexpression of the histidine triad nucleotide-binding protein 2 protects cardiac function in the adult mice after acute myocardial infarction. PG - e13439 LID - 10.1111/apha.13439 [doi] AB - 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. CI - (c) 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd. FAU - Fan, Mengkang AU - Fan M AUID- ORCID: 0000-0002-8994-6825 AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. AD - Department of Cardiovascular, Affiliated Hospital of Nantong University, Jiangsu, China. FAU - Chen, Zhangwei AU - Chen Z AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Huang, Yin AU - Huang Y AD - Department of Geriatric Medicine, Affiliated Hospital of Nantong University, Jiangsu, China. FAU - Xia, Yan AU - Xia Y AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Chen, Ao AU - Chen A AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Lu, Danbo AU - Lu D AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Wu, Yuan AU - Wu Y AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Zhang, Ning AU - Zhang N AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Zhang, Peipei AU - Zhang P AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Li, Su AU - Li S AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Chen, Jinxiang AU - Chen J AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Zhang, Yingmei AU - Zhang Y AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Sun, Aijun AU - Sun A AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Zou, Yunzeng AU - Zou Y AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Hu, Kai AU - Hu K AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Qian, Juying AU - Qian J AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. FAU - Ge, Junbo AU - Ge J AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200121 PL - England TA - Acta Physiol (Oxf) JT - Acta physiologica (Oxford, England) JID - 101262545 RN - 0 (Mitochondrial Proteins) RN - 0U46U6E8UK (NAD) RN - EC 3.- (Hydrolases) RN - EC 3.9.1.- (HINT2 protein, mouse) SB - IM MH - Animals MH - Heart/*physiology MH - Hydrolases/*metabolism MH - Male MH - Membrane Potential, Mitochondrial MH - Mice MH - Mice, Inbred C57BL MH - Mitochondrial Proteins/*metabolism MH - Molecular Docking Simulation MH - Myocardial Infarction/*metabolism MH - Myocytes, Cardiac/metabolism MH - NAD/metabolism MH - Oxygen Consumption MH - Positron Emission Tomography Computed Tomography OTO - NOTNLM OT - heart failure OT - mitochondrial function OT - myocardial infarction OT - nicotinamide adenine dinucleotide EDAT- 2020/01/05 06:00 MHDA- 2021/06/03 06:00 CRDT- 2020/01/05 06:00 PHST- 2019/11/02 00:00 [received] PHST- 2019/12/14 00:00 [revised] PHST- 2019/12/31 00:00 [accepted] PHST- 2020/01/05 06:00 [pubmed] PHST- 2021/06/03 06:00 [medline] PHST- 2020/01/05 06:00 [entrez] AID - 10.1111/apha.13439 [doi] PST - ppublish SO - Acta Physiol (Oxf). 2020 Apr;228(4):e13439. doi: 10.1111/apha.13439. Epub 2020 Jan 21.