SIRT6 suppresses phenylephrine-induced cardiomyocyte hypertrophy though inhibiting p300.
SIRT6 is a member of the sirtuin family of class III histone deacetylases. It plays important roles in regulating genomic stability, metabolism, stress response and aging. Our previous study has revealed that SIRT6 attenuates myocardial hypertrophy by inhibiting NF-κB activation, but the related molecular mechanisms remain to be clarified. In the present study, we showed that the p300 acetylase was involved in the protective effect of SIRT6 against phenylephrine (PE)-induced cardiomyocyte hypertrophy. In cultured neonatal rat cardiomyocytes, the expression and activity of SIRT6 declined following PE treatment, while the protein level of p300 was upregulated. PE triggered significant hypertrophic responses as manifested by increase in cellular surface area and expression of hypertrophy marker genes, which could be blocked by SIRT6 overexpression. Mechanistically, SIRT6 reduced p300 protein expression via promoting its degradation, which could be attributed to the suppression of PI3K/Akt signaling. The downregulation of p300 protein level by SIRT6 subsequently decreased the acetylation and transcriptional activity of NF-κB p65 subunit. These findings help to further understand mechanisms underlying the anti-hypertrophic role of SIRT6 and suggest the potential of SIRT6 as a therapeutic target for cardiac hypertrophy.
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
Peiye
P
Shen
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
Xiaojun
X
Feng
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; School of Medicine, Xizang Minzu University, Xianyang 712082, Shaanxi, PR China.
Xiaoying
X
Zhang
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
Xiaoyang
X
Huang
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
Shenglan
S
Liu
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
Xia
X
Lu
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
Jingyan
J
Li
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
Jia
J
You
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
Jing
J
Lu
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, PR China; Guangdong Provincial Key Laboratory of Construction Foundation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, PR China.
Zhuoming
Z
Li
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, PR China; Guangdong Provincial Key Laboratory of Construction Foundation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, PR China. Electronic address: yejt@mail.sysu.edu.cn.
Jiantao
J
Ye
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, PR China; Guangdong Provincial Key Laboratory of Construction Foundation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, PR China. Electronic address: liupq@mail.sysu.edu.cn.
Peiqing
P
Liu
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism*; D002478:Cells, Cultured; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics; D010656:Phenylephrine; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D034741:RNA, Small Interfering; D010656:Phenylephrine; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; D037761:Sirtuins; C560607:sirtuin 6, rat
Cardiac hypertrophy; Phenylephrine; SIRT6; p300; p65