The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun.
The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun.
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作者：
胰岛素样生长因子（IGF）-Akt信号的异常激活与各种疾病的发展有关，包括心力衰竭。然而，调节该信号传导途径活化的分子机制尚未完全了解。在这里，我们表明，sirtuin 6（SIRT 6），核组蛋白脱乙酰酶，在染色质水平的功能，直接减弱IGF-Akt信号。SIRT 6缺陷小鼠发生心脏肥大和心力衰竭，而SIRT 6转基因小鼠受到保护免受肥大刺激，表明SIRT 6作为心脏肥大的负调节剂。SIRT 6缺陷小鼠心脏显示IGF信号相关基因及其下游靶标的过度活化。在机制上，SIRT 6通过与c-Jun相互作用并使组蛋白3在Lys 9（H3 K9）处脱乙酰化来结合并抑制IGF信号传导相关基因的启动子。我们还发现SIRT 6在人类衰竭心脏中的表达减少。这些发现揭示了SIRT 6和IGF-Akt信号之间的新联系，并暗示SIRT 6在心脏肥大和衰竭的发展中起作用。
Abnormal activation of insulin-like growth factor (IGF)-Akt signaling is implicated in the development of various diseases, including heart failure. However, the molecular mechanisms that regulate activation of this signaling pathway are not completely understood. Here we show that sirtuin 6 (SIRT6), a nuclear histone deacetylase, functions at the level of chromatin to directly attenuate IGF-Akt signaling. SIRT6-deficient mice developed cardiac hypertrophy and heart failure, whereas SIRT6 transgenic mice were protected from hypertrophic stimuli, indicating that SIRT6 acts as a negative regulator of cardiac hypertrophy. SIRT6-deficient mouse hearts showed hyperactivation of IGF signaling–related genes and their downstream targets. Mechanistically, SIRT6 binds to and suppresses the promoter of IGF signaling–related genes by interacting with c-Jun and deacetylating histone 3 at Lys9 (H3K9). We also found reduced SIRT6 expression in human failing hearts. These findings disclose a new link between SIRT6 and IGF-Akt signaling and implicate SIRT6 in the development of cardiac hypertrophy and failure.
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影响因子：
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