title: SIRT6 suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy.
abstract: Reduction in autophagy has been reported to contribute to the pathogenesis of cardiac hypertrophy. However, the molecular pathways leading to impaired autophagy at the presence of hypertrophic stimuli remain to be elucidated. The present study aimed to investigate the role of sirtuin 6 (SIRT6), a sirtuin family member, in regulating cardiomyocyte autophagy, and its implication in prevention of cardiac hypertrophy. Primary neonatal rat cardiomyocytes (NRCMs) or Sprague-Dawley (SD) rats were submitted to isoproterenol (ISO) treatment, and then the hypertrophic responses and changes in autophagy activity were measured. The influence of SIRT6 on autophagy was observed in cultured NRCMs with gain- and loss-of-function approaches to regulate SIRT6 expression, and further confirmed in vivo by intramyocardial delivery of an adenovirus vector encoding SIRT6 cDNA. In addition, the involvement of SIRT6-mediated autophagy in attenuation of cardiomyocyte hypertrophy induced by ISO was determined basing on genetic or pharmaceutical disruption of autophagy, and the underlying mechanism was preliminarily explored. ISO-caused cardiac hypertrophy accompanying with a significant decrease in autophagy activity. SIRT6 overexpression enhanced autophagy in NRCMs and in rat hearts, whereas knockdown of SIRT6 by RNA interference led to suppression of cardiomyocyte autophagy. Furthermore, the protective effect of SIRT6 against ISO-stimulated hypertrophy was associated with induction of autophagy. SIRT6 promoted nuclear retention of forkhead box O3 transcription factor possibly via attenuating Akt signaling, which was responsible for autophagy activation. Our findings revealed that SIRT6 positively regulates autophagy in cardiomyocytes, which may help to ameliorate ISO-induced cardiac hypertrophy.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Duanping
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Huiqi
authors.initials: H
authors.lastname: Hong
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Cui
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Si
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Guangzhou Research Institute of Snake Venom, Guangzhou Medical College, Guangzhou, Guangdong, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Shaorui
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Zhuoming
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China. Electronic address: yejt@mail.sysu.edu.cn.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China. Electronic address: liupq@mail.sysu.edu.cn.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D007545:Isoproterenol; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D037761:Sirtuins / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051057:Proto-Oncogene Proteins c-akt; D037761:Sirtuins; C560607:sirtuin 6, rat; D007545:Isoproterenol