SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy
SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy
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SIRT6 抑制心肌细胞肥大中 NFATc4 的表达和激活
DOI：
10.3389/fphar.2018.01519
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发表时间：
2019-01-08
影响因子：
5.6
通讯作者：
Liu, Peiqing
中科院分区：
文献类型：
--
作者：
Li, Zhenzhen;Zhang, Xiaoying;Liu, Peiqing
NFATc4是活化T细胞核因子（Nuclear Factor of Activated T Cells，NFATs）转录因子家族的成员，在心肌肥厚的发生发展中起着关键作用。NFATc4被钙调神经磷酸酶去磷酸化，并从细胞质转移到细胞核，以调节肥大基因（如脑钠肽（BNP））的表达。本研究鉴定了SIRT6，NAD+依赖性III类组蛋白去乙酰化酶的重要亚型，是心肌细胞肥大中NFATc4的负调节剂。在苯肾上腺素（PE）诱导的肥大心肌细胞模型中，通过腺病毒感染或质粒转染过表达SIRT6抑制NFATc4的蛋白和mRNA表达，提高其磷酸化水平，阻止其核积聚，随后抑制其转录活性并下调其靶基因BNP。相反，没有脱乙酰酶活性的SIRT6突变体（H133Y）没有表现出这些作用，表明SIRT6对NFATc4的抑制作用依赖于其脱乙酰酶活性。此外，NFATc4补充逆转了SIRT6过表达对抑制BNP表达的影响，而NFATc4沉默恢复了SIRT6缺陷对上调BNP的影响。从机制上讲，SIRT6和NFATc4之间的相互作用可能促进SIRT6对NFATc4的脱乙酰化，从而阻止NFATc4的活化。总之，本研究揭示SIRT6抑制NFATc4的表达和激活。这些结果为SIRT6的抗心肌肥厚作用提供了更多的证据，并提示SIRT6是心肌肥厚的潜在治疗靶点。
NFATc4, a member from the Nuclear Factor of Activated T cells (NFATs) transcription factor family, plays a pivotal role in the development of cardiac hypertrophy. NFATc4 is dephosphorylated by calcineurin and translocated from the cytoplasm to the nucleus to regulate the expression of hypertrophic genes, like brain natriuretic polypeptide (BNP). The present study identified SIRT6, an important subtype of NAD+ dependent class III histone deacetylase, to be a negative regulator of NFATc4 in cardiomyocyte hypertrophy. In phenylephrine (PE)-induced hypertrophic cardiomyocyte model, overexpression of SIRT6 by adenovirus infection or by plasmid transfection repressed the protein and mRNA expressions of NFATc4, elevated its phosphorylation level, prevented its nuclear accumulation, subsequently suppressed its transcriptional activity and downregulated its target gene BNP. By contrast, mutant of SIRT6 without deacetylase activity (H133Y) did not demonstrate these effects, suggesting that the inhibitory effect of SIRT6 on NFATc4 was dependent on its deacetylase activity. Moreover, the effect of SIRT6 overexpression on repressing BNP expression was reversed by NFATc4 replenishment, whereas the effect of SIRT6 deficiency on upregulating BNP was recovered by NFATc4 silencing. Mechanistically, interactions between SIRT6 and NFATc4 might possibly facilitate the deacetylation of NFATc4 by SIRT6, thereby preventing the activation of NFATc4. In conclusion, the present study reveals that SIRT6 suppresses the expression and activation of NFATc4. These findings provide more evidences of the anti-hypertrophic effect of SIRT6 and suggest SIRT6 as a potential therapeutic target for cardiac hypertrophy.