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KMID : 0620920180500070083
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Experimental & Molecular Medicine
2018 Volume.50 No. 7 p.83 ~ p.83
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PP2A negatively regulates the hypertrophic response by dephosphorylating HDAC2 S394 in the heart
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Yoon So-My
Kook Tae-Won
Min Hyun-Ki
Kwon Duk-Hwa
Cho Young-Kuk
Kim Mi-Ra
Shin Se-Ra
Joung Ho-Souk
Jeong Seung-Hoon
Lee Su-Min
Kang Ga-Eun
Park Yun-Chul
Kim Yong-Sook
Ahn Young-Keun
McMullen Julie R.
Gergs Ulrich
Neumann Joachim
Kim Kyung-Keun
Kim Jung-Chul
Nam Kwang-Il
Kim Young-Kook
Kook Hyun
Eom Gwang-Hyeon
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Abstract
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Cardiac hypertrophy occurs in response to increased hemodynamic demand and can progress to heart failure. Identifying the key regulators of this process is clinically important. Though it is thought that the phosphorylation of histone deacetylase (HDAC) 2 plays a crucial role in the development of pathological cardiac hypertrophy, the detailed mechanism by which this occurs remains unclear. Here, we performed immunoprecipitation and peptide pull-down assays to characterize the functional complex of HDAC2. Protein phosphatase (PP) 2?A was confirmed as a binding partner of HDAC2. PPP2CA, the catalytic subunit of PP2A, bound to HDAC2 and prevented its phosphorylation. Transient overexpression of PPP2CA specifically regulated both the phosphorylation of HDAC2 S394 and hypertrophy-associated HDAC2 activation. HDAC2 S394 phosphorylation was increased in a dose-dependent manner by PP2A inhibitors. Hypertrophic stresses, such as phenylephrine in vitro or pressure overload in vivo, caused PPP2CA to dissociate from HDAC2. Forced expression of PPP2CA negatively regulated the hypertrophic response, but PP2A inhibitors provoked hypertrophy. Adenoviral delivery of a phosphomimic HDAC2 mutant, adenovirus HDAC2 S394E, successfully blocked the anti-hypertrophic effect of adenovirus-PPP2CA, implicating HDAC2 S394 phosphorylation as a critical event for the anti-hypertrophic response. PPP2CA transgenic mice were protected against isoproterenol-induced cardiac hypertrophy and subsequent cardiac fibrosis, whereas simultaneous expression of HDAC2 S394E in the heart did induce hypertrophy. Taken together, our results suggest that PP2A is a critical regulator of HDAC2 activity and pathological cardiac hypertrophy and is a promising target for future therapeutic interventions.
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KEYWORD
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Experimental models of disease, Phosphorylation
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