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Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming\u2010induced physiological hypertrophy and pressure overload\u2010induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid\u2010related orphan nuclear receptor\u2010\u03b1 (ROR\u03b1) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming\u2010induced physiological hypertrophic murine hearts. In vivo and in vitro loss\u2010of\u2010function experiments indicated that ROR\u03b1 deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti\u2010hypertrophic effects of melatonin. Mechanistically, ROR\u03b1 mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese\u2010dependent superoxide dismutase (MnSOD) via binding to the ROR\u03b1 response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro\u2010hypertrophic effects of ROR\u03b1 deficiency, while MnSOD silencing abolished the anti\u2010hypertrophic effects of ROR\u03b1 overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti\u2010hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a ROR\u03b1\u2010dependent manner.<\/jats:p>","DOI":"10.1111\/jpi.12579","type":"journal-article","created":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T19:19:54Z","timestamp":1554751194000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor ROR\u03b1 signaling"],"prefix":"10.1111","volume":"67","author":[{"given":"Longwei","family":"Xu","sequence":"first","affiliation":[{"name":"State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology Renji Hospital, School of Medicine, Shanghai Cancer Institute Shanghai Jiao 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