CKIP-1 Inhibits Cardiac Hypertrophy by Regulating Class II Histone Deacetylase Phosphorylation Through Recruiting PP2A
CKIP-1 Inhibits Cardiac Hypertrophy by Regulating Class II Histone Deacetylase Phosphorylation Through Recruiting PP2A
复制标题
CKIP-1 通过招募 PP2A 调节 II 类组蛋白脱乙酰酶磷酸化来抑制心脏肥大
DOI：
10.1161/circulationaha.112.102780
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发表时间：
2012-12-18
期刊：
影响因子：
37.8
通讯作者：
Li, Yingxian
中科院分区：
文献类型：
--
作者：
Ling, Shukuan;Sun, Qiao;Li, Yingxian
背景-持续的心脏压力超负荷引起的心肌肥厚和病理性重构经常导致心力衰竭。酪蛋白激酶-2相互作用蛋白-1（CKIP-1）已被鉴定为细胞增殖、分化和凋亡的重要调节因子。然而，CKIP-1在心脏中的生理作用是unknow.Methods和Results-The超声心动图和组织学的结果表明，CKIP-1缺陷小鼠表现出自发性心脏肥大与年龄和超敏反应压力超负荷诱导的病理性心脏肥大，以及。CKIP-1心脏特异性过表达的转基因小鼠对压力超负荷的心脏肥大表现出抵抗力。GST pull-down和免疫共沉淀实验结果显示CKIP-1和组蛋白去乙酰化酶4（HDAC 4）之间存在相互作用，通过这种相互作用，CKIP-1和HDAC 4协同抑制肌细胞特异性增强因子2C的转录活性。CKIP-1通过与磷酸酶2A的催化亚基直接相互作用，增强磷酸酶2A的催化亚基与HDAC 4的结合，促进HDAC 4的去磷酸化。结论CKIP-1通过募集蛋白磷酸酶2A，上调HDAC 4的去磷酸化，从而抑制心肌肥厚。这些结果证明了CKIP-1的独特功能，通过其调节HDAC 4去磷酸化和胎儿心脏基因表达的能力来抑制心脏肥大。（循环。2012;126：3028-3040）。
Background-Sustained cardiac pressure overload-induced hypertrophy and pathological remodeling frequently leads to heart failure. Casein kinase-2 interacting protein-1 (CKIP-1) has been identified to be an important regulator of cell proliferation, differentiation, and apoptosis. However, the physiological role of CKIP-1 in the heart is unknown.Methods and Results-The results of echocardiography and histology demonstrate that CKIP-1-deficient mice exhibit spontaneous cardiac hypertrophy with aging and hypersensitivity to pressure overload-induced pathological cardiac hypertrophy, as well. Transgenic mice with cardiac-specific overexpression of CKIP-1 showed resistance to cardiac hypertrophy in response to pressure overload. The results of GST pull-down and coimmunoprecipitation assays showed the interaction between CKIP-1 and histone deacetylase 4 (HDAC4), through which they synergistically inhibited transcriptional activity of myocyte-specific enhancer factor 2C. By directly interacting with the catalytic subunit of phosphatase 2A, CKIP-1 overexpression enhanced the binding of catalytic subunit of phosphatase-2A to HDAC4 and promoted HDAC4 dephosphorylation.Conclusions-CKIP-1 was found to be an inhibitor of cardiac hypertrophy by upregulating the dephosphorylation of HDAC4 through the recruitment of protein phosphatase 2A. These results demonstrated a unique function of CKIP-1, by which it suppresses cardiac hypertrophy through its capacity to regulate HDAC4 dephosphorylation and fetal cardiac genes expression. (Circulation. 2012;126:3028-3040.)