Medical Research Center for Gene Regulation, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju, South Korea.
Circulation. 2011 May 31;123(21):2392-403. doi: 10.1161/CIRCULATIONAHA.110.003665. Epub 2011 May 16.
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-2α1 (CK2α1)-dependent phosphorylation of HDAC2 S394 is required for the development of cardiac hypertrophy.
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 CK2α1 short interfering RNA. Hypertrophic stimuli led CK2α1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and isoproterenol-administered mice. CK2α1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2α1 caused hypertrophy in cardiomyocytes, whereas chemical inhibitors of both CK2 and HDAC as well as HDAC2 S394A blunted it. Hypertrophy in CK2α1-transgenic mice was exaggerated by crossing these mice with wild-type-HDAC2-overexpressing mice. By contrast, however, it was blocked when CK2α1-transgenic mice were crossed with HDAC2 S394A-transgenic mice.
We have demonstrated a novel mechanism in the development of cardiac hypertrophy by which CK2 activates HDAC2 via phosphorylating HDAC2 S394.
心肌肥厚的特征是胎儿基因表达的转录重编程，组蛋白去乙酰化酶（HDACs）与这些基因的调控密切相关。我们之前证明，I 类 HDAC 之一的 HDAC2 的激活介导了心肌肥厚。在这里，我们表明，酪蛋白激酶-2α1（CK2α1）依赖性磷酸化 HDAC2 S394 是心肌肥厚发展所必需的。
肥大刺激物磷酸化 HDAC2 S394，这对于其酶活性是必需的，因此在新生大鼠心肌细胞或异丙肾上腺素处理的小鼠心脏中发展出肥厚表型。过表达野生型 HDAC2 的转基因小鼠表现出心肌肥厚，而表达磷酸化抗性 HDAC2 S394A 的则没有。与年龄匹配的正常人类心脏相比，肥厚型心肌病患者的 HDAC2 S394 磷酸化显著增加。HDAC2 S394 的肥厚诱导磷酸化及其酶活性均被 CK2 抑制剂或 CK2α1 短发夹 RNA 完全阻断。肥大刺激物导致 CK2α1 被激活，其化学抑制剂在苯肾上腺素处理的心肌细胞和异丙肾上腺素处理的小鼠中均阻断了肥大。CK2α1 转基因小鼠发生肥大，用 HDAC 抑制剂 Trichostatin A 处理可减轻肥大。CK2α1 的过表达导致心肌细胞肥大，而 CK2 和 HDAC 的化学抑制剂以及 HDAC2 S394A 则使其减弱。将这些小鼠与野生型 HDAC2 过表达小鼠杂交可使 CK2α1 转基因小鼠的肥大加剧，而将 CK2α1 转基因小鼠与 HDAC2 S394A 转基因小鼠杂交则可阻断其肥大。
我们通过证明 CK2 通过磷酸化 HDAC2 S394 激活 HDAC2 来发展心肌肥厚的新机制。
