Differential effects of histone deacetylase inhibitors on hypertrophic signaling pathways

Cardiac hypertrophy is an independent risk factor for the development of heart failure. Although it was originally assumed that hypertrophy was a necessary compensatory response of the heart to increased load, more recent evidence suggests that contractile function can be maintained in the absence of cardiomyocyte hypertrophy. Thus, inhibiting the onset of hypertrophy, or reversing established hypertrophic growth, may be of therapeutic value. A number of intracellular signaling pathways have been implicated as mediators of this response. Recently, we showed that histone deacetylase inhibitors (HDAC-I), a novel class of antineoplastic agents, suppressed hypertrophy of cultured neonatal rat ventricular myocytes. Here, we extend this investigation to demonstrate that hypertrophic signaling pathways are differentially regulated by HDAC-I. Using phospho-specific antibodies, we found that the HDAC-I trichostatin A (TSA) blocked agonist-dependent activation of both c-Jun N-terminal kinase (JNK) as well as extracellular signal-regulated kinase-5 (ERK-5), which are mitogen-activated protein kinases (MAPKs) implicated in cardiac pathology. Likewise, activity of the pro-hypertrophic calcineurin-NFAT pathway was dramatically reduced by TSA treatment, as determined by decreased expression of the calcineurin-responsive gene encoding modulatory calcineurin inhibitory protein 1 (MCIP1). In contrast, HDAC-I had little or no effect on various components of the protein kinase C (PKC) network. These findings reveal unanticipated roles for histone deacetylases in control of cytoplasmic signaling cascades and provide a mechanism for HDAC-I-mediated repression pathological cardiac growth.