STAT3 Suppression Is Involved in the Protective Effect of SIRT6 Against Cardiomyocyte Hypertrophy
STAT3 Suppression Is Involved in the Protective Effect of SIRT6 Against Cardiomyocyte Hypertrophy
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DOI：
10.1097/fjc.0000000000000404
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发表时间：
2016-09
影响因子：
3
通讯作者：
Xiaoying Zhang;Wei Li;P. Shen;Xiao-jun Feng;Z. Yue;Jing Lu;J. You;Jing-yan Li;Hui Gao
中科院分区：
文献类型：
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作者：
Xiaoying Zhang;Wei Li;P. Shen;Xiao-jun Feng;Z. Yue;Jing Lu;J. You;Jing-yan Li;Hui Gao
摘要：信号换能器和转录激活因子3 （STAT3）的激活在心脏肥厚和心力衰竭的发展中起着至关重要的作用。Sirtuin 6 （SIRT6）保护心肌细胞免于肥厚。本研究关注SIRT6和STAT3在心肌细胞肥厚调节中的关联。在苯肾上腺素（PE）诱导的肥厚心肌细胞模型和异丙肾上腺素诱导的肥厚心肌大鼠模型中，STAT3 mRNA和蛋白表达及其酪氨酸705磷酸化水平（P-STAT3）均显著升高。相比之下，SIRT6的去乙酰化活性减弱，但不改变其蛋白表达。此外，PE增强了STAT3和P-STAT3的核定位，提示STAT3在心肌细胞肥大过程中被激活。腺病毒感染诱导的SIRT6过表达通过降低STAT3的mRNA和蛋白水平、抑制其转录活性和阻碍其靶基因的表达来抑制STAT3的激活。此外，SIRT6过表达对消除pe诱导的肥厚性生物标志物（如心房利钠因子和脑利钠肽）表达的影响被STAT3过表达逆转。同样，SIRT6敲低诱导的心房利钠因子和脑利钠肽上调通过STAT3沉默被逆转。这些观察结果表明SIRT6的抗肥厚作用涉及STAT3的抑制。综上所述，SIRT6可阻止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。
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.