Casein Kinase-2α1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart
Casein Kinase-2α1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart
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DOI：
10.1161/circulationaha.110.003665
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发表时间：
2011-05-31
期刊：
影响因子：
37.8
通讯作者：
Kook, Hyun
中科院分区：
文献类型：
--
作者：
Eom, Gwang Hyeon;Cho, Young Kuk;Kook, Hyun
背景-心肌肥大的特征是胎儿基因表达的转录重编程，组蛋白脱乙酰酶（HDAC）与这些基因的调控密切相关。我们先前证明了HDAC 2（I类HDAC之一）的激活介导肥大。在这里，我们表明，酪蛋白激酶-2 α 1（CK 2 α 1）依赖磷酸化HDAC 2 S394的发展所需的心脏hypertrophysic.Methods和Results-Hypertrophic刺激磷酸化HDAC 2 S394，这是必要的，其酶促激活，因此在大鼠新生心肌细胞或在异丙肾上腺素管理的小鼠心脏肥大表型的发展。过度表达野生型HDAC 2的转基因小鼠表现出心脏肥大，而表达抗磷酸化HDAC 2 S394 A的小鼠则没有。与年龄匹配的正常人心脏相比，肥厚型心肌病患者HDAC 2 S394磷酸化水平显著升高。肥大诱导的HDAC 2 S394磷酸化及其酶活性被CK 2阻断剂或CK 2 α 1短干扰RNA完全阻断。肥大刺激导致CK 2 α 1被激活，其化学抑制剂阻断了苯肾上腺素处理的心肌细胞和异丙肾上腺素给药小鼠的肥大。CK 2 α 1转基因小鼠出现肥大，给予HDAC抑制剂阿司他汀A可减轻肥大。CK 2 α 1的过度表达导致心肌细胞肥大，而CK 2和HDAC以及HDAC 2 S394 A的化学抑制剂使其钝化。然而，相比之下，当CK 2 α 1-转基因小鼠与HDAC 2 S394 A-转基因migrations.Conclusions-We杂交时，它被阻断了，我们已经证明了一种新的机制，在心脏肥大的发展中，CK 2通过磷酸化HDAC 2 S394激活HDAC 2。（循环。2011;123：2392-2403）。
Background-Cardiac hypertrophy is characterized by transcriptional reprogramming of fetal gene expression, and histone deacetylases (HDACs) are tightly linked to the regulation of those genes. We previously demonstrated that activation of HDAC2, 1 of the class I HDACs, mediates hypertrophy. Here, we show that casein kinase-2 alpha 1 (CK2 alpha 1)-dependent phosphorylation of HDAC2 S394 is required for the development of cardiac hypertrophy.Methods and Results-Hypertrophic stimuli phosphorylated HDAC2 S394, which was necessary for its enzymatic activation, and therefore the development of hypertrophic phenotypes in rat neonatal cardiomyocytes or in isoproterenol-administered mice hearts. Transgenic mice overexpressing HDAC2 wild type exhibited cardiac hypertrophy, whereas those expressing phosphorylation-resistant HDAC2 S394A did not. Compared with that in age-matched normal human hearts, phosphorylation of HDAC2 S394 was dramatically increased in patients with hypertrophic cardiomyopathy. Hypertrophy-induced phosphorylation of HDAC2 S394 and its enzymatic activity were completely blocked either by CK2 blockers or by CK2 alpha 1 short interfering RNA. Hypertrophic stimuli led CK2 alpha 1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and isoproterenol-administered mice. CK2 alpha 1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2 alpha 1 caused hypertrophy in cardiomyocytes, whereas chemical inhibitors of both CK2 and HDAC as well as HDAC2 S394A blunted it. Hypertrophy in CK2 alpha 1-transgenic mice was exaggerated by crossing these mice with wild-type-HDAC2-overexpressing mice. By contrast, however, it was blocked when CK2 alpha 1-transgenic mice were crossed with HDAC2 S394A-transgenic mice.Conclusions-We have demonstrated a novel mechanism in the development of cardiac hypertrophy by which CK2 activates HDAC2 via phosphorylating HDAC2 S394. (Circulation. 2011;123:2392-2403.)