Postnatal cardiac myocytes respond to stress signals by hypertrophic growth and activation of a fetal gene program. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals. To further define the roles of HDACs in cardiac hypertrophy, we analyzed the effects of HDAC inhibitors on the responsiveness of primary cardiomyocytes to hypertrophic agonists. Paradoxically, HDAC inhibitors imposed a dose-dependent blockade to hypertrophy and fetal gene activation. We conclude that distinct HDACs play positive or negative roles in the control of cardiomyocyte hypertrophy. HDAC inhibitors are currently being tested in clinical trials as anti-cancer agents. Our results suggest that these inhibitors may also hold promising clinical value as therapeutics for cardiac hypertrophy and heart failure.Postnatal cardiac myocytes undergo hypertrophic growth in response to a variety of stress signals (reviewed in Ref. 1). The hypertrophic response is characterized by increases in myocyte size and protein synthesis, assembly and organization of sarcomeres, and activation of a fetal gene program. Although traditionally considered an adaptive response to pathological signaling, chronic expression of fetal cardiac genes in the heart can result in maladaptive changes in cardiac contractility and calcium handling that culminate in dilated cardiomyopathy, heart failure, and sudden death from arrhythmias (2). Moreover, increasing evidence in rodent models indicates that cardiac function is preserved when hypertrophy is inhibited in the face of stress signaling, pointing to the potential importance of therapeutic strategies for modulating the hypertrophic process (3-9).Recent studies have revealed key roles for chromatin-modifying enzymes in the control of cardiac hypertrophy (10 -12). The structure of chromatin is governed by the acetylation state of nucleosomal histones (13,14). Acetylation of histone tails by histone acetyltransferases (HATs) 1 results in relaxation of nucleosomal structure and transcriptional activation. Acetylated histones also serve as targets for binding of bromo-domain proteins that possess HAT activity and act as transcriptional activators. The actions of HATs are opposed by histone deacetylases (HDACs), which deacetylate nucleosomal histones, thereby promoting chromatin condensation and transcriptional repression.Mammalian HDACs can be divided into three classes based on their similarity with three yeast HDACs (reviewed in Refs. 15 and 16). Class I HDACs (HDACs 1, 2, 3, and 8) are expressed ubiquitously and consist mainly of a deacetylase domain. Members of class II (HDACs 4, 5, 7, and 9) are highly expressed in striated muscle and brain and have an extended N terminus in addition to the catalytic domain. Class III HDACs resemble the yeast HDAC Sir2, which is activated by nicotinamide adenine dinucleotide (17).Class II HDACs interact with a variety of positive and negative cofactors as well as other ...

No abstract