title: Melatonin alleviates postinfarction cardiac remodeling and dysfunction by inhibiting Mst1.
abstract: Melatonin reportedly protects against several cardiovascular diseases including ischemia/reperfusion (I/R), atherosclerosis, and hypertension. The present study investigated the effects and mechanisms of melatonin on cardiomyocyte autophagy, apoptosis, and mitochondrial injury in the context of myocardial infarction (MI). We demonstrated that melatonin significantly alleviated cardiac dysfunction after MI. Four weeks after MI, echocardiography and Masson staining indicated that melatonin notably mitigated adverse left ventricle remodeling. The mechanism may be associated with increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin significantly inhibited Mst1 phosphorylation while promoting Sirt1 expression after MI, which indicates that Mst1/Sirt1 signaling may serve as the downstream target of melatonin. We thus constructed a MI model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1-/-) mice. The absence of Mst1 abolished the favorable effects of melatonin on cardiac injury after MI. Consistently, melatonin administration did not further increase autophagy, decrease apoptosis, or alleviate mitochondrial integrity and biogenesis in Mst1 knockout mice subjected to MI injury. These results suggest that melatonin alleviates postinfarction cardiac remodeling and dysfunction by upregulating autophagy, decreasing apoptosis, and modulating mitochondrial integrity and biogenesis. The attributed mechanism involved, at least in part, Mst1/Sirt1 signaling.
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Wanrong
authors.initials: W
authors.lastname: Man
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*; D000099317:Hippo Kinases
chemical_list: D008550:Melatonin; D017346:Protein Serine-Threonine Kinases; D056564:Sirtuin 1; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C470545:Sirt1 protein, mouse
keywords: autophagy; mammalian Ste20-like kinase 1; melatonin; myocardial infarction; silent information regulator 1