Abstract-Diverse cardiac diseases induce cardiac hypertrophy, which leads to dilatation and heart failure. We previously reported that hypertrophy can be blocked by class I histone deacetylase (HDAC) inhibitor, which prompted us to investigate the regulatory mechanism of class I HDACs. Cardiac hypertrophy was introduced by aortic banding, by infusion of isoproterenol or angiotensin II, or by swimming. Hypertrophic stimuli transiently elevated the activity of histone deacetylase-2 (Hdac2), a class I HDAC. In cardiomyocytes, forced expression of Hdac2 simulated hypertrophy in an Akt-dependent manner, whereas enzymatically inert Hdac2 H141A failed to do so. Hypertrophic stimuli induced the expression of heat shock protein (Hsp)70. The induced Hsp70 physically associated with and activated Hdac2. Hsp70 overexpression produced a hypertrophic phenotype, which was blocked either by siHdac2 or by a dominant negative Hsp70⌬ABD. In Hsp70.1 Ϫ/Ϫ mice, cardiac hypertrophy and Hdac2 activation were significantly blunted. Heat shock either to cardiomyocytes or to mice activated Hdac2 and induced hypertrophy. However, heat shock-induced Hdac2 activation was blunted in the cardiomyocytes isolated from Hsp70.1 Ϫ/Ϫ mice. These results suggest that the induction of Hsp70 in response to diverse hypertrophic stresses and the ensuing activation of HDAC2 trigger cardiac hypertrophy, emphasizing HSP70/HDAC2 as a novel mechanism regulating hypertrophy. Key Words: cardiac hypertrophy Ⅲ class I histone deacetylases Ⅲ histone deacetylase 2 Ⅲ heat shock protein 70 Ⅲ Hsp70.1 Ϫ/Ϫ mice C ardiac hypertrophy is a response, either adaptive or maladaptive, to pressure or volume overload, mutations, or loss of contractile mass. Hypertrophic growth accompanies many forms of heart disease, including ischemic diseases, myocardial infarction, hypertension, aortic stenosis, and valvular dysfunctions. Although the initial hypertrophic responses seem to be an adaptation to those stimuli, the sustained stress may lead to cardiomyopathy and heart failure, a major cause of human morbidity and mortality. However, few interventions have proven effective in blocking the hypertrophy or in preventing the transition to congestive heart failure.Cardiomyocyte hypertrophy is characterized by an increase in individual myocyte size, enhanced protein synthesis, and heightened organization of the sarcomere, 1 which are regulated by activation of heart-specific transcription factors such as GATA4, MEF2, and immediate early genes like c-jun and c-fos. 2 The subsequent reactivation of the fetal gene program and repression of adult cardiac genes are closely related to the deterioration of heart function in hypertrophy.Recently, modulation of gene transcription by altering chromatin structure, especially by adding or removing acetyl groups to histone tails, has been implicated in diverse human pathologies, including cardiac hypertrophy. 3 Histone deacetylases (HDACs), which remove the acetyl group, repress downstream gene expression. Although HDACs are divided into 4 familie...

Background-Cardiac hypertrophy is characterized by transcriptional reprogramming of fetal gene expression, and histone deacetylases (HDACs) are tightly linked to the regulation of those genes. We previously demonstrated that activation of HDAC2, 1 of the class I HDACs, mediates hypertrophy. Here, we show that casein kinase-2␣1 (CK2␣1)-dependent phosphorylation of HDAC2 S394 is required for the development of cardiac hypertrophy. Methods and Results-Hypertrophic stimuli phosphorylated HDAC2 S394, which was necessary for its enzymatic activation, and therefore the development of hypertrophic phenotypes in rat neonatal cardiomyocytes or in isoproterenoladministered mice hearts. Transgenic mice overexpressing HDAC2 wild type exhibited cardiac hypertrophy, whereas those expressing phosphorylation-resistant HDAC2 S394A did not. Compared with that in age-matched normal human hearts, phosphorylation of HDAC2 S394 was dramatically increased in patients with hypertrophic cardiomyopathy. Hypertrophy-induced phosphorylation of HDAC2 S394 and its enzymatic activity were completely blocked either by CK2 blockers or by CK2␣1 short interfering RNA. Hypertrophic stimuli led CK2␣1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and isoproterenol-administered mice. CK2␣1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2␣1 caused hypertrophy in cardiomyocytes, whereas chemical inhibitors of both CK2 and HDAC as well as HDAC2 S394A blunted it. Hypertrophy in CK2␣1-transgenic mice was exaggerated by crossing these mice with wild-type-HDAC2-overexpressing mice. By contrast, however, it was blocked when CK2␣1-transgenic mice were crossed with HDAC2 S394A-transgenic mice. Conclusions-We have demonstrated a novel mechanism in the development of cardiac hypertrophy by which CK2 activates HDAC2 via phosphorylating HDAC2 S394. (Circulation. 2011;123:2392-2403.)Key Words: hypertrophy Ⅲ casein kinase 2 Ⅲ histone deacetylase 2 S394 Ⅲ phosphorylation Ⅲ transgenic mice C ardiac hypertrophy, an increase in the size of cardiomyocytes, is often caused by diverse pathological conditions such as myocardial infarction, hypertension, aortic stenosis, and valvular dysfunction. Although cardiac hypertrophy itself is an initial adaptive process, uncorrected continuous stimuli often lead the heart to heart failure. Because heart failure is a main cause of human mortality, many researchers are eager to develop interventions to reverse cardiac hypertrophy or to prevent the transition to congestive heart failure. Editorial see p 2341 Clinical Perspective on p 2403Posttranslational modifications of histones are closely involved in diverse biological processes through the regulation of transcription of downstream target genes. 1,2 Among these modifications, the acetylation status of the chromatin mediates the epigenetic regulation of gene expression. Two opposing groups of enzymes, histone acetyltransferase and hi...

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp lthough primary cardiac hypertrophy can result from genetic abnormalities, most cases in the clinical situation are secondary to pressure or volume overload, to mutations of sarcomere proteins, or to loss of contractile mass because of a prior infarction. 1 When cardiac hypertrophy persists for a long time without intensive care, the resulting deterioration in diastolic function often leads to congestive heart failure. 2 Great advances in surgical techniques and medical management of congenital heart diseases have dramatically improved the survival of affected patients over the past decades. However, with many patients with congenital heart disease now surviving until adulthood, right ventricular hypertrophy (RVH) has drawn much attention. 3 It is well known that several congenital heart diseases often cause RVH, even though various surgical or interventional corrections have been developed. Examples are pressure overload RVH caused by right ventricular (RV) outflow tract obstruction after total correction of tetralogy of Fallot, pulmonary stenosis, the atrial switch operation for transposition of the great arteries, and congenitally corrected transposition of the great arteries, and systemic RVH after the Fontan operation. Other conditions are volume overload RVH caused by atrial septal defect, tricuspid regurgitation, and pulmonary regurgitation. 3,4 Development of RVH should be carefully monitored and both medical prevention and treatment should be considered.Currently, afterload-reducing agents, β-adrenergic blockers, inotropics, and diuretics are used in the treatment of cardiac dysfunction, including cardiac hypertrophy. It is widely accepted that several angiotensin-converting enzyme (ACE) inhibitors have clinical benefits in the treatment of left ventricular hypertrophy (LVH) 5-7 but there is much debate over the ideal medical management of RVH 4 because the primary

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Oxytocin stimulates the cardiomyogenesis of embryonic stem cells and adult cardiac stem cells. We previously reported that oxytocin has a promigratory effect on umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). In this study, UCB-MSCs were cultured with oxytocin and examined for their therapeutic effect in an infarcted heart. UCB-MSCs were pretreated with 100 nM oxytocin and cardiac markers were assessed by immunofluorescence staining. Next, oxytocin-supplemented USC-MSCs (OT-USCs) were cocultured with hypoxia/reoxygenated neonatal rat cardiomyocytes and cardiac markers and dye transfer were then examined. For the in vivo study, ischemia/reperfusion was induced in rats, and phosphate-buffered saline (group 1), 1-day OT-USCs (group 2), or 7-day OT-USCs (group 3) were injected into the infarcted myocardium. Two weeks after injection, histological changes and cardiac function were examined. UCB-MSCs expressed connexin 43 (Cnx43), cardiac troponin I (cTnI), and α-sarcomeric actin (α-SA) after oxytocin supplementation and coculture with cardiomyocytes. Functional gap junction formation was greater in group 3 than in groups 1 and 2. Cardiac fibrosis and macrophage infiltration were lower in group 3 than in group 2. Restoration of Cnx43 expression was greater in group 3 than in group 2. Cnx43- and cTnI-positive OT-USCs in the peri-infarct zone were observed in group 2 and more frequently in group 3. The ejection fraction (EF) was increased in groups 2 and 3 in 2 weeks. The improved EF was sustained for 4 weeks only in group 3. Our findings suggest that the supplementation of UCB-MSCs with oxytocin can contribute to the cardiogenic potential for cardiac repair.