Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3β activity
Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3β activity
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DOI：
10.1038/nm1552
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发表时间：
2007-03-01
期刊：
影响因子：
82.9
通讯作者：
Epstein, Jonathan A.
中科院分区：
文献类型：
--
作者：
Trivedi, Chinmay M.;Luo, Yang;Epstein, Jonathan A.
在成人心脏中，各种应激诱导与心肌细胞肥大和心力衰竭相关的胎儿基因程序的重新表达。在这里，我们表明，组蛋白去乙酰化酶-2（Hdac 2）调节许多胎儿心脏亚型的表达。hdac 2缺陷或化学组蛋白脱乙酰酶（HDAC）抑制防止胎儿基因的重新表达，并减弱心脏肥大的心脏暴露于肥大刺激。抗肥大性与编码肌醇多磷酸-5-磷酸酶f（Inpp 5 f）的基因表达增加相关，导致糖原合成酶激酶3b（Gsk 3b）通过胸腺瘤病毒原癌基因（Akt）和3-磷酸肌醇依赖性蛋白激酶-1（Pdk 1）失活而组成性激活。相反，Hdac 2转基因小鼠具有与失活的Gsk 3b相关的增大的肥大。化学抑制激活Gsk 3b允许Hdac 2缺陷的成年人变得敏感的肥大刺激。这些结果表明，Hdac 2是心脏中HDAC抑制剂的重要分子靶标，并且Hdac 2和Gsk 3b是调节途径的组分，为治疗心脏肥大和心力衰竭提供了有吸引力的治疗靶标。
In the adult heart, a variety of stresses induce re-expression of a fetal gene program in association with myocyte hypertrophy and heart failure. Here we show that histone deacetylase-2 (Hdac2) regulates expression of many fetal cardiac isoforms. Hdac2 deficiency or chemical histone deacetylase ( HDAC) inhibition prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3b (Gsk3b) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide- dependent protein kinase-1 (Pdk1). In contrast, Hdac2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3b. Chemical inhibition of activated Gsk3b allowed Hdac2-deficient adults to become sensitive to hypertrophic stimulation. These results suggest that Hdac2 is an important molecular target of HDAC inhibitors in the heart and that Hdac2 and Gsk3b are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.