SIRT6 suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy

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• 作者：Jing Lu^a ; Duanping Sun^a ; Zhiping Liu^a ; Min Li^a ; Huiqi Hong^a ; Cui Liu^a ; Si Gao^a ; Hong Li^b ; Yi Cai^c ; Shaorui Chen^a ; Zhuoming Li^a ; Jiantao Ye^a ; ^{yejt@mail.sysu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Peiqing Liu^a ; ^{liupq@mail.sysu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Atgs ; autophagy-related genes ; ANF ; atrial natriuretic factor ; BNP ; brain natriuretic polypeptide ; FoxO3 ; forkhead box O3 ; LC3 ; microtubule-associated protein 1 light chain 3 ; IF ; immunofluorescence ; NRCMs ; neonatal rat cardiomyocytes ; ISO ; isoproterenol ; TEM ; transmission electron microscopy ; HE ; hematoxylin-eosin ; MDC ; monodansylcadaverine ; 3-MA ; 3-methyladenine ; β-MHC ; β-myosin heavy chain
• 刊名：Translational Research
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：172
• 期：Complete
• 页码：96-112.e6
• 全文大小：4398 K

文摘

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.