Li Zhenzhen, Zhang Xiaoying, Guo Zhen, Zhong Yao, Wang Panxia, Li Jingyan, Li Zhuoming, Liu Peiqing
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Front Pharmacol. 2019 Jan 8;9:1519. doi: 10.3389/fphar.2018.01519. eCollection 2018.
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.
活化T细胞核因子（NFATs）转录因子家族成员NFATc4在心肌肥大的发展中起关键作用。NFATc4被钙调神经磷酸酶去磷酸化，并从细胞质转移到细胞核，以调节肥厚相关基因的表达，如脑钠肽（BNP）。本研究确定NAD依赖性Ⅲ类组蛋白去乙酰化酶的重要亚型SIRT6是心肌细胞肥大中NFATc4的负调节因子。在苯肾上腺素（PE）诱导的肥厚心肌细胞模型中，通过腺病毒感染或质粒转染过表达SIRT6可抑制NFATc4的蛋白质和mRNA表达，提高其磷酸化水平，阻止其核内蓄积，随后抑制其转录活性并下调其靶基因BNP。相比之下，无去乙酰化酶活性的SIRT6突变体（H133Y）未表现出这些作用，表明SIRT6对NFATc4的抑制作用依赖于其去乙酰化酶活性。此外，NFATc4补充可逆转SIRT6过表达对BNP表达的抑制作用，而NFATc4沉默可恢复SIRT6缺乏对BNP上调的作用。机制上，SIRT6与NFATc4之间的相互作用可能促进SIRT6对NFATc4的去乙酰化，从而阻止NFATc4的激活。总之，本研究表明SIRT6抑制NFATc4的表达和激活。这些发现为SIRT6的抗肥厚作用提供了更多证据，并提示SIRT6作为心肌肥大的潜在治疗靶点。
