SIRT6 suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy

• Published in: Translational research : the journal of laboratory and clinical medicine 2016-06, Vol.172, p.96-112.e6
• Main Authors: Lu, Jing, Sun, Duanping, Liu, Zhiping, Li, Min, Hong, Huiqi, Liu, Cui, Gao, Si, Li, Hong, Cai, Yi, Chen, Shaorui, Li, Zhuoming, Ye, Jiantao, Liu, Peiqing
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Autophagy; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - prevention & control; Cells, Cultured; Forkhead Box Protein O3 - metabolism; Internal Medicine; Isoproterenol; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - ultrastructure; Proto-Oncogene Proteins c-akt - metabolism; Rats, Sprague-Dawley; Signal Transduction; Sirtuins - metabolism; Vacuoles - metabolism; Vacuoles - ultrastructure
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2016.03.002

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 SIRT6, a sirtuin family member, in regulating cardiomyocyte autophagy, and its implication in prevention of cardiac hypertrophy. Primary neonatal rat cardiomyocytes (NRCMs) or 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, as well as 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 (FoxO3) 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.