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This study was designed to investigate the role of Flt3 activation in sympathetic hyperactivity\u2010induced cardiac hypertrophy and its mechanisms through autophagy and mitochondrial dynamics\n                    <jats:italic>.<\/jats:italic>\n                    In vivo, cardiac hypertrophy was established by subcutaneous injection of isoprenaline (6\u00a0mg\/kg\u00b7day) in C57BL\/6 mice for 7 consecutive days. The Flt3\u2010ligand intervention was launched 2\u2009h prior to isoprenaline each day. In vitro, experiments of cardiomyocyte hypertrophy, autophagy, and mitochondrial dynamics were performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that the expression level of Flt3 protein was significantly increased in the hypertrophic myocardium provoked by isoprenaline administration. Flt3\u2010ligand intervention alleviated isoprenaline\u2010induced cardiac oxidative stress, hypertrophy, fibrosis, and contractile dysfunction. Isoprenaline stimulation impaired autophagic flux in hypertrophic mouse hearts, supported by the accumulation of LC3II and P62 proteins, while Flt3\u2010ligand restored the impairment of autophagic flux. Flt3 activation normalized the imbalance of mitochondrial fission and fusion in the hearts of mice evoked by isoprenaline as evidenced by the neutralization of elevated mitochondrial fission markers and reduced mitochondrial fusion markers. In NRCMs, Flt3\u2010ligand treatment attenuated isoprenaline\u2010stimulated hypertrophy, which was abolished by a Flt3\u2010specific blocker AC220. Activating Flt3 reversed isoprenaline\u2010induced autophagosome accumulation and impairment of autophagic flux probably by enhancing SIRT1 expression and consequently TFEB nuclear translocation. Flt3 activation improved the imbalance of mitochondrial dynamics induced by isoprenaline in NRCMs through the SIRT1\/P53 pathway. Activation of Flt3 mitigated ISO\u2010stimulated hypertrophy probably involves the restoration of autophagic flux and balance of mitochondrial dynamics. Therefore, activation of Flt3 attenuates isoprenaline\u2010induced cardiac hypertrophy in vivo and in vitro, the potential mechanism probably attributes to SIRT1\/TFEB\u2010mediated autophagy promotion and SIRT1\/P53\u2010mediated mitochondrial dynamics balance. These findings suggest that activation of Flt3 may be a novel target for protection against cardiac remodeling and heart failure during sympathetic hyperactivity.\n                  <\/jats:p>","DOI":"10.1096\/fj.202200419rr","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T08:56:30Z","timestamp":1669625790000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Activation of\n                    <scp>FMS<\/scp>\n                    \u2010like tyrosine kinase 3 protects against isoprenaline\u2010induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics"],"prefix":"10.1096","volume":"36","author":[{"given":"Xixi","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Xi'an Jiaotong University Health Science Center  Xi'an 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University Health Science Center  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Xi'an Jiaotong University Health Science Center  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaowa","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Xi'an Jiaotong University Health Science Center  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Xi'an Jiaotong University Health Science Center  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical 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