title: STAT3 Suppression Is Involved in the Protective Effect of SIRT6 Against Cardiomyocyte Hypertrophy.
abstract: The activation of signal transducer and activator of transcription 3 (STAT3) is critical for the development of cardiac hypertrophy and heart failure. Sirtuin 6 (SIRT6) protects cardiomyocytes from hypertrophy. This study focused on the association between SIRT6 and STAT3 in the regulation of cardiomyocyte hypertrophy. In the phenylephrine (PE)-induced hypertrophic cardiomyocyte model and in the hearts of isoprenaline-induced cardiac hypertrophic rat model, the mRNA and protein expressions of STAT3 and its phosphorylated level at tyrosine 705 (P-STAT3) were significantly increased. By contrast, the deacetylation activity of SIRT6 was weakened without altering its protein expression. In addition, the nuclear localization of STAT3 and P-STAT3 was enhanced by PE, suggesting that STAT3 was activated in cardiomyocyte hypertrophy. Adenovirus infection-induced SIRT6 overexpression repressed the activation of STAT3 by decreasing its mRNA and protein levels, by suppressing its transcriptional activity, and by hindering the expressions of its target genes. Moreover, the effect of SIRT6 overexpression on eliminating PE-induced expressions of hypertrophic biomarkers, such as atrial natriuretic factor and brain natriuretic peptide, was reversed by STAT3 overexpression. Likewise, SIRT6 knockdown-induced upregulation of atrial natriuretic factor and brain natriuretic peptide was reversed by STAT3 silencing. These observations suggest that the antihypertrophic effect of SIRT6 involves STAT3 suppression. In conclusion, SIRT6 prevents PE-induced activation of STAT3 in cardiomyocyte hypertrophy; the inhibitory effect of SIRT6 on STAT3 contributes to cardiac protection.
authors.affiliation: *Department of Pharmacology and Toxicology, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; †Department of Pharmacology, School of Medicine, Xizang Minzu University, Shaanxi, China; and ‡Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Peiye
authors.initials: P
authors.lastname: Shen
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Feng
authors.forename: Zhongbao
authors.initials: Z
authors.lastname: Yue
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Jia
authors.initials: J
authors.lastname: You
authors.forename: Jingyan
authors.initials: J
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Shi
authors.initials: S
authors.lastname: Fang
authors.forename: Zhuoming
authors.initials: Z
authors.lastname: Li
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000378:metabolism*; D002478:Cells, Cultured; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D037761:Sirtuins / Q000096:biosynthesis*; D016896:Treatment Outcome
chemical_list: D002316:Cardiotonic Agents; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D037761:Sirtuins; C560607:sirtuin 6, rat