Zhang Xiaoying, Li Wei, Shen Peiye, Feng Xiaojun, Yue Zhongbao, Lu Jing, You Jia, Li Jingyan, Gao Hui, Fang Shi, Li Zhuoming, Liu Peiqing
*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.
J Cardiovasc Pharmacol. 2016 Sep;68(3):204-14. doi: 10.1097/FJC.0000000000000404.
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.
信号转导子与转录激活子3（STAT3）的激活对心脏肥大和心力衰竭的发展至关重要。沉默调节蛋白6（SIRT6）可保护心肌细胞免于肥大。本研究聚焦于SIRT6与STAT3在心肌细胞肥大调节中的关联。在苯肾上腺素（PE）诱导的肥大心肌细胞模型以及异丙肾上腺素诱导的心脏肥大大鼠模型心脏中，STAT3的mRNA和蛋白表达及其酪氨酸705位点的磷酸化水平（P-STAT3）显著增加。相比之下，SIRT6的去乙酰化活性减弱，但其蛋白表达未改变。此外，PE增强了STAT3和P-STAT3的核定位，提示STAT3在心肌细胞肥大中被激活。腺病毒感染诱导的SIRT6过表达通过降低STAT3的mRNA和蛋白水平、抑制其转录活性以及阻碍其靶基因的表达来抑制STAT3的激活。此外，STAT3过表达逆转了SIRT6过表达对消除PE诱导的肥大生物标志物如心房钠尿肽和脑钠尿肽表达的作用。同样，STAT3沉默逆转了SIRT6敲低诱导的心房钠尿肽和脑钠尿肽上调。这些观察结果表明，SIRT6的抗肥大作用涉及对STAT3的抑制。总之，SIRT6可防止PE诱导的心肌细胞肥大中STAT3的激活；SIRT6对STAT3的抑制作用有助于心脏保护。
