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Forkhead box protein O6 (FoxO6) is a key transcription factor involved in many biological processes. This study aimed to explore the role of FoxO6 in cardiac hypertrophy. Three groups of mice were established: wild\u2010type, FoxO6 knockout, and FoxO6\u2010overexpressing. The mice received daily administration of angiotensin\u2010II (Ang\u2010II) or saline for 4 weeks, after which they were examined for cardiac hypertrophy, fibrosis, and function. Elevated cardiac expression of FoxO6 was observed in Ang\u2010II\u2010treated mice. FoxO6 deficiency attenuated contractile dysfunction and cardiac remodeling, including cardiomyocyte hypertrophy and fibroblast proliferation and differentiation. Conversely, FoxO6 overexpression aggravated the cardiomyopathy and heart dysfunction. Further studies identified kinesin family member 15 (Kif15) as downstream molecule of FoxO6. Kif15 inhibition attenuated the aggravating effect of FoxO6 overexpression. In vitro, FoxO6 overexpression increased Kif15 expression in cardiomyocytes and elevated the concentration of transforming growth factor\u2010\u03b21 (TGF\u2010\u03b21) in the medium where fibroblasts were grown, exhibiting increased proliferation and differentiation, while FoxO6 knockdown attenuated this effect. Cardiac\u2010derived FoxO6 promoted pathological cardiac remodeling induced by aggravated afterload largely by activating the Kif15\/TGF\u2010\u03b21 axis. This result further complements the mechanisms of communication among different cells in the heart, providing novel therapeutic targets for heart failure.<\/jats:p>","DOI":"10.1002\/mco2.383","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T09:08:23Z","timestamp":1696410503000},"source":"Crossref","is-referenced-by-count":7,"title":["Forkhead box O6 (FoxO6) promotes cardiac pathological remodeling and dysfunction by activating Kif15\u2013TGF\u2010\u03b21 under aggravated afterload"],"prefix":"10.1002","volume":"4","author":[{"given":"Bing","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery Xijing Hospital The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0311-720X","authenticated-orcid":false,"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery 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