CKIP-1 Inhibits Cardiac Hypertrophy by Regulating Class II Histone Deacetylase Phosphorylation through Recruiting PP2A
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 demonstrated that CKIP-1-deficient mice exhibit spontaneous cardiac hypertrophy with aging as well as hypersensitivity to pressure overload-induced pathological cardiac hypertrophy. Transgenic mice with cardiac-specific over-expression of CKIP-1 showed resistance to cardiac hypertrophy in response to pressure overload. The results of GST pull down and Co-immunoprecipitation assays showed the interaction between CKIP-1 and HDAC4, through which they synergistically inhibited transcriptional activity of MEF2C. By directly interacting with the catalytic subunit of phosphatase-2A (PP2AC), CKIP-1 over-expression enhanced the binding of PP2AC to HDAC4 and promoted HDAC4 dephosphorylation.
Conclusions—CKIP-1 was found to be an inhibitor of cardiac hypertrophy by up-regulating the dephosphorylation of HDAC4 through the recruitment of PP2A. 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.
- Received February 29, 2012.
- Accepted November 1, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited