title: SIRT1 mediates the protective function of Nkx2.5 during stress in cardiomyocytes.
abstract: Nkx2.5 plays protective roles in cardiac homeostasis and survival in the postnatal hearts. However, the underlying molecular mechanisms that mediate the protective functions of Nkx2.5 remain unknown. Here, we showed that Nkx2.5 was downregulated in response to various stresses and was required for protection against the stress-induced apoptosis of cardiomyocytes. SIRT1, a member of the sirtuin family of proteins, was found to be a direct transcriptional target of Nkx2.5 and was required for the Nkx2.5-mediated protection of cardiomyocytes from doxorubicin (DOX)-induced apoptosis. Moreover, using chromatin immunoprecipitation assays, we found that Nkx2.5 was able to bind to the SIRT1 promoter and that this binding was significantly decreased in DOX-treated mouse hearts. Furthermore, the cardiac-specific overexpression of SIRT1 decreased the DOX-induced apoptosis of cardiomyocytes in SIRT1 transgenic mouse hearts compared with the hearts of their wild-type littermates. These findings demonstrate that SIRT1 acts as a direct transcriptional target of Nkx2.5 that maintains cardiomyocyte homeostasis and survival.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing, 100005, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Yun-Biao
authors.initials: YB
authors.lastname: Lu
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Liang
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: She
authors.forename: Zhu-Qin
authors.initials: ZQ
authors.lastname: Zhang
authors.forename: Rui-Feng
authors.initials: RF
authors.lastname: Yang
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Mao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: De-Long
authors.initials: DL
authors.lastname: Hao
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Wei
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; C524161:Nkx2-5 protein, rat; D014157:Transcription Factors; D004317:Doxorubicin; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1