CKIP-1 Inhibits Cardiac Hypertrophy by Regulating Class II Histone Deacetylase Phosphorylation Through Recruiting PP2A

• DOI: 10.1161/circulationaha.112.102780
• Publication Date: 2012-11-15T02:01:58Z
• Authors: Shukuan Ling; Qiao Sun; Yuheng Li; Luo Zhang; Pengfei Zhang; Xiaogang Wang; Chunyan Tian; Qi Li; Jinping Song; Hongju Liu; Guanghan Kan; Hongqing Cao; Zengming Huang; Jielin Nie; Yanqiang Bai; Shanguang Chen; Yinghui Li; Fuchu He; Lingqiang Zhang; Yingxian Li
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Transcription, Genetic; MEF2 Transcription Factors; Myocardium; Age Factors; Cardiomegaly; Histone Deacetylases; 3. Good health; Mice; 03 medical and health sciences; Myogenic Regulatory Factors; Animals; Protein Phosphatase 2; Phosphorylation; Carrier Proteins

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.