PP2A negatively regulates the hypertrophic response by dephosphorylating HDAC2 S394 in the heart

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. A regulatory mechanism that controls how cardiac muscle responds to stress could inform development of new therapies for preventing heart failure. Physiological stimuli ranging from heavy exercise to heart attack can induce hypertrophy, an increase in cardiac muscle mass that is initially beneficial but can lead to organ failure. Researchers led by Gwang Hyeon Eom and Hyun Kook at the Chonnam National University Biomedical Research Center, Hwasungun, South Korea have found that an enzyme called protein phosphatase 2A (PP2A) keeps cardiac hypertrophy in check. PP2A binds to and inhibits a second protein known as HDAC2, which would otherwise stimulate the hypertrophic response to stress. The researchers have identified the biochemical mechanism by which PP2A inactivates HDAC2, and demonstrate that this inhibition effectively protects against hypertrophic cardiac damage in mice, revealing a possible avenue for clinical intervention.