Small heterodimer partner blocks cardiac hypertrophy by interfering with GATA6 signaling.

RATIONALE: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA-binding domain. Through interactions with other transcription factors, SHP regulates diverse biological events, including glucose metabolism in liver. However, the role of SHP in adult heart diseases has not yet been demonstrated. OBJECTIVE: We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy. METHODS AND RESULTS: The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP-null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of hypertrophy in cardiomyocytes. SHP reduced the protein amount of Gata6 and, by direct physical interaction with Gata6, interfered with the binding of Gata6 to GATA-binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an antidiabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced antihypertrophic effect was attenuated either by SHP small interfering RNA in cardiomyocytes or in SHP-null mice. CONCLUSIONS: These results establish SHP as a novel antihypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced antihypertrophic response.

Transient complete atrioventricular block in a preterm neonate with congenital myotonic dystrophy: case report.

Congenital myotonic dystrophy (CMD) is an inherited neuromuscular disorder with cardiac rhythm abnormalities that may occur as a child grows. No report has described complete atrioventricular (AV) block detected in a neonate with CMD. We report a floppy infant of 31(+4) weeks gestation with complete AV block at birth, who was diagnosed with CMD by Southern analysis. She recovered from complete AV block 32 hr after temporary transcutaneous pacing was applied. To the best our knowledge, this is the first recorded case of a complete AV block accompanied by CMD during the neonatal period. When a newborn has a complete AV block, the physician should consider the possibility of the CMD and conduct a careful physical examination.

Estrogen-related receptor gamma induces cardiac hypertrophy by activating GATA4.

Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor that has biological roles mainly in metabolism and that controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. The functional roles of ERRγ in the development of cardiac hypertrophy were examined in primary cultured cardiomyocytes and in animal models. ERRγ expression was increased in hearts from human hypertrophic cardiomyopathy patients and in both cellular and animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ bound directly to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182, an inverse agonist of ERRγ, completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic.

Right ventricular myocardial performance index is decreased with severe pressure-overload cardiac hypertrophy in young rats.

Although the right ventricular (RV) myocardial performance index (MPI) usually is increased in the presence of RV dysfunction and pressure overload, debate continues over the correlation between the RV MPI and functional derangement in patients with RV pressure-overload congenital heart disease (CHD). To address this controversy, this study took serial measurements of the RV MPI in addition to invasive RV hemodynamic measurements during the acute stage of mild to severe pressure overload. Right ventricle pressure overload was induced by partial pulmonary arterial banding (PAB) in 3-week-old rats. The rats were divided into two groups: mild pulmonary stenosis (PS) group (20-40 % stenosis; n = 20) and severe PS group (40-70 % stenosis; n = 28). Sham-treated animals (sham group; n = 30) underwent the same surgical procedure without PAB. Pressure-overload RV hypertrophy was documented by weighing the heart, by evaluating echocardiograms, and by evaluating cardiac hypertrophy-associated gene expression. The RV MPI was checked 1, 2, 3, 5, and 8 weeks after PAB. The MPI was calculated as the sum of the isovolumic contraction time and the isovolumic relaxation time (IRT) divided by the ejection time. The RV MPI of the mild PS group did not differ significantly from that of the sham group. The RV MPI of the severe PS group, however, was lower than that of the sham group (0.27 ± 0.01 vs 0.29 ± 0.01) 2 to 8 weeks after PAB: 0.19 ± 0.01 at 2 weeks (P < 0.001), 0.16 ± 0.01 at 3 weeks (P < 0.001), 0.20 ± 0.01 at 5 weeks (P = 0.021), and 0.18 ± 0.01 at 8 weeks (P < 0.001) after PAB. The decreased RV MPI was associated with decreased IRT and increased ejection time. RV hypertrophy contributes to the decrease in the RV MPI in the severe pressure-overload condition.

Effects of Dextrose Supplementation on Chloral Hydrate Sedation: A Double-Blinded, Randomized, Prospective Study.

Sedation plays a crucial role in successful pediatric imaging, and chloral hydrate is commonly used for this purpose. However, the challenges associated with chloral hydrate administration, such as its unpleasant taste and potential induction of vomiting, remain a concern. Sweet oral solutions have emerged as potential solutions for reducing distress and providing analgesia. This study compared the efficacy of dextrose combined with chloral hydrate with that of conventional sedation methods. This prospective, double-blind, randomized controlled clinical study enrolled 160 pediatric outpatients scheduled for echocardiography. Chloral hydrate syrup (100 mg/mL) was supplemented with a dextrose solution (dextrose group) or distilled water (control group) in a 1:10 volume ratio. The sedation achievement time, Skeie scale score, revised Face, Legs, Activity, Cry, and Consolability (FLACC) score, and side effects (nausea, vomiting, hypoxia, and respiratory depression) were assessed. No significant difference in average time to achieve sedation was observed between the dextrose and control groups (24.4±17.8 vs. 24.7±17.1 min, p=0.92). Both groups demonstrated similar levels of sedation according to the Skeie scale and mean revised FLACC score. Although the occurrence rates of nausea and vomiting had no significant differences, the dextrose group had no cases of vomiting in children aged >24 months compared to the control group, which had three cases (30%). In conclusion, the addition of dextrose to chloral hydrate did not significantly affect sedation time, anxiety, pain reduction, or occurrence of gastrointestinal complications during sedation.

Circular RNA circSMAD4 regulates cardiac fibrosis by targeting miR-671-5p and FGFR2 in cardiac fibroblasts.

Heart failure is a leading cause of death and is often accompanied by activation of quiescent cardiac myofibroblasts, which results in cardiac fibrosis. In this study, we aimed to identify novel circular RNAs that regulate cardiac fibrosis. We applied transverse aortic constriction (TAC) for 1, 4, and 8 weeks in mice. RNA sequencing datasets were obtained from cardiac fibroblasts isolated by use of a Langendorff apparatus and then further processed by use of selection criteria such as differential expression and conservation in species. CircSMAD4 was upregulated by TAC in mice or by transforming growth factor (TGF)-ß1 in primarily cultured human cardiac fibroblasts. Delivery of si-circSMAD4 attenuated myofibroblast activation and cardiac fibrosis in mice treated with isoproterenol (ISP). si-circSmad4 significantly reduced cardiac fibrosis and remodeling at 8 weeks. Mechanistically, circSMAD4 acted as a sponge against the microRNA miR-671-5p in a sequence-specific manner. miR-671-5p was downregulated during myofibroblast activation and its mimic form attenuated cardiac fibrosis. miR-671-5p mimic destabilized fibroblast growth factor receptor 2 (FGFR2) mRNA in a sequence-specific manner and interfered with the fibrotic action of FGFR2. The circSMAD4-miR-671-5p-FGFR2 pathway is involved in the differentiation of cardiac myofibroblasts and thereby the development of cardiac fibrosis.

Casein kinase-2α1 induces hypertrophic response by phosphorylation of histone deacetylase 2 S394 and its activation in the heart.

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-2α1 (CK2α1)-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 isoproterenol-administered 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 CK2α1 short interfering RNA. Hypertrophic stimuli led CK2α1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and isoproterenol-administered mice. CK2α1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2α1 caused hypertrophy in cardiomyocytes, whereas chemical inhibitors of both CK2 and HDAC as well as HDAC2 S394A blunted it. Hypertrophy in CK2α1-transgenic mice was exaggerated by crossing these mice with wild-type-HDAC2-overexpressing mice. By contrast, however, it was blocked when CK2α1-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.

Priming of mesenchymal stem cells with oxytocin enhances the cardiac repair in ischemia/reperfusion injury.

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.

Neurologic adverse events following influenza A (H1N1) vaccinations in children.

BACKGROUND: Since the monovalent pandemic influenza A (H1N1) vaccine was recommended worldwide in October 2009, there has been a shortage of pediatric clinical data for post-vaccine neurologic adverse events (NAE), including Guillain-Barré syndrome. We reviewed pediatric NAE data following H1N1 vaccinations and for patients with peripheral neuropathy, we followed their progress. METHODS: In our single-center study, we retrospectively reviewed 14 cases of children who visited the Division of Pediatric Neurology in the Department of Pediatrics of Chonnam National University Hospital due to NAE following monovalent influenza A (H1N1) vaccination between November 2009 and March 2010. RESULTS: Clinical diagnoses for major NAE included: polyneuropathy in the extremities (11/14, 78.6%), sensory mononeuropathy with numbness in the left fibula area (1/14, 7.1%), Bell's palsy (1/14, 7.1%) and recent-onset acute headache only (1/14, 7.1%). Therefore, most patients were diagnosed as having peripheral neuropathy (13/14, 92.9%), and two met the Brighton Collaboration Guillain-Barré syndrome definition criteria for level 3 (the lowest level of diagnostic certainty). CONCLUSIONS: Post-vaccine NAE were mainly motor weakness due to polyneuropathy, which had a good prognosis of complete improvement within a few months without sequelae.

Mosaic ring chromosome 6 in an infant with significant patent ductus arteriosus and multiple congenital anomalies.

The clinical features of ring chromosome 6 include central nervous system anomalies, growth retardation, facial dysmorphism and other congenital anomalies. Ring chromosome 6 occurs rarely and manifests as various phenotypes. We report the case of mosaic ring chromosome 6 by conventional karyotyping in a 7-day-old male infant diagnosed with a large patent ductus arteriosus (PDA) with hypoplasia of aortic valve and aortic arch. These have not been previously reported with ring chromosome 6. He recovered from heart failure symptoms after ligation of the PDA. He showed infantile failure to thrive and delayed milestone in a follow-up evaluation. To the best of our knowledge, this is the first report of a Korean individual with ring chromosome 6 and hemodynamically significant PDA.

Recurrent plastic bronchitis in a child with 2009 influenza A (H1N1) and influenza B virus infection.

Plastic bronchitis is an uncommon disorder characterized by the formation of bronchial casts. It is associated with congenital heart disease or pulmonary disease. In children with underlying conditions such as allergy or asthma, influenza can cause severe plastic bronchitis resulting in respiratory failure. A review of the literature showed nine cases of plastic bronchitis with H1N1 including this case. We report a case of a child with recurrent plastic bronchitis with eosinophilic cast associated with influenza B infection, who had recovered from plastic bronchitis associated with an influenza A (H1N1) virus infection 5 months previously. To the best of our knowledge, this is the first case of recurrent plastic bronchitis related to influenza viral infection. If patients with influenza virus infection manifest acute respiratory distress with total lung atelectasis, clinicians should consider plastic bronchitis and early bronchoscopy should be intervened. In addition, management for underlying disease may prevent from recurrence of plastic bronchitis.

Platelet Indices as Diagnostic Marker for Kawasaki Disease.

Various candidate biomarkers have been investigated for the early and accurate diagnosis of Kawasaki disease (KD). We aimed to evaluate platelet activity using platelet indices (PI) in patients with KD or simple febrile illness to determine whether these indices might support a diagnosis of KD. Another objective of the study was to delineate the changes in PI from the acute to convalescent phases of KD. A total of 225 patients with complete KD (cKD), 110 with incomplete KD (iKD), and 71 with simple febrile illness (control) were enrolled. PI included mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT). We serially measured the serum PI four times for each patient with KD from the acute to convalescent phases: on D0 (day of intravenous immunoglobulin (IVIG) treatment) and repeated on days 2 (D2), 14 (D14), and 56 (D56) after IVIG therapy. Data from the control group were collected during the acute stage of the disease (D0). The platelet counts in the cKD (341±103×103/mm3) and iKD (374±135×103/mm3) at diagnosis were higher than the control group (290±128×103/mm3). The PCT in the cKD (0.284±0.085%) and iKD (0.313±0.109%) groups at diagnosis were also higher than the control group (0.246±0.108%). However, the MPV and PDW levels in the KD group were not statistically significant. Therefore, platelet count and PCT are adjuvant parameters for the differential diagnosis of KD from a simple febrile illness.

Overexpression of Prohibitin 2 Protein is Associated with Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia.

Cytogenetically normal acute myeloid leukemia (CN-AML) accounts for 40%-50% of all AML cases. Despite advances in understanding the molecular pathophysiology of CN-AML, its clinical outcome remains unsatisfactory and unpredictable. To investigate its clinical implication in CN-AML, we measured the expression of prohibitin 2 (PHB2) using immunohistochemical staining (IHCS) of paraffin-embedded bone marrow sections from 134 CN-AML patients. IHCS results were semi-quantitatively scored. Clinical outcome was analyzed in comparison with other prognostic markers, including NPM1 polymorphism and FLT3 internal tandem duplication, and WT1 and BAALC mRNA expression. Except for BAALC mRNA expression, the known molecular markers showed no prognostic effect in the CN-AML patients. PHB2 protein overexpression was significantly associated with adverse prognosis in CN-AML patients. The PHB2 protein expression status may serve as an independent prognostic indicator in CN-AML.

Serum Ferritin as a Diagnostic Biomarker for Kawasaki Disease.

Diagnosis of Kawasaki disease (KD) is occasionally delayed because it is solely based on clinical symptoms. Previous studies have attempted to identify diagnostic biomarkers for KD. Recently, patients with KD were reported to have elevated serum ferritin levels. We investigated the usefulness of the serum ferritin level as a diagnostic biomarker for distinguishing KD from other acute febrile illnesses. Blood samples were obtained from pediatric patients with KD (N=77) and those with other acute febrile illnesses (N=32) between December 2007 and June 2011 for measuring various laboratory parameters, including serum ferritin levels. In patients with KD, laboratory tests were performed at diagnosis and repeated at 2, 14, and 56 days after intravenous immunoglobulin treatment. At the time of diagnosis, serum ferritin levels in patients with KD (188.8 µg/L) were significantly higher than those in patients with other acute febrile illnesses (106.8 µg/L, P=0.003). The serum ferritin cut-off value of 120.8 µg/L effectively distinguished patients with KD from those with other acute febrile illnesses, with a sensitivity and specificity of 74.5% and 83.3%, respectively. Serum ferritin may be a useful biomarker to distinguish KD from other acute febrile illnesses.

Activation of histone deacetylase 2 by inducible heat shock protein 70 in cardiac hypertrophy.

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 Hsp70DeltaABD. In Hsp70.1(-/-) 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(-/-) 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.

Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats.

BACKGROUND: Although right ventricular hypertrophy (RVH) is an adaptive process to stresses such as outflow tract obstruction, uncorrected persistent RVH often results in failure of the right ventricle or even the left ventricle. Histone deacetylase (HDAC) inhibitors can effectively prevent or block left ventricular hypertrophy, so the present study compared the effects of sodium valproate, an HDAC inhibitor, with those of captopril, an angiotensin-converting enzyme inhibitor, on RVH. METHODS AND RESULTS: RVH was induced in rats by pulmonary artery banding (PAB) or monocrotaline (MCT) injection, and then either sodium valproate or captopril was administered. PAB or MCT injection caused a marked increase in the size of RV after 2 weeks, which was documented by weighing it, by evaluating echocardiograms or electrocardiograms, or by examining cardiac hypertrophy-associated gene expression. Sodium valproate significantly reduced RVH induced by either PAB or MCT injection. Interestingly, however, captopril failed to do so. CONCLUSIONS: In the present study sodium valproate, but not captopril, was effective in blocking RVH induced by PAB or MCT injection, which suggests that HDAC inhibitors may be a novel therapy for RVH.

Author Correction: PP2A negatively regulates the hypertrophic response by dephosphorylating HDAC2 S394 in the heart.

After the publication of this article, the authors noticed an error in one of the grant numbers (2015R1A2A1A05001708) in the Acknowledgements section.

Spontaneous Regression of Cardiac Rhabdomyoma Presenting as Severe Left Ventricular Inlet Obstruction in a Neonate with Tuberous Sclerosis.

Cardiac rhabdomyoma can be subclinical or have a fatal presentation according to the onset age and involved site, size, and degree of invasion. Although most cardiac rhabdomyomas become smaller with time, emergency intervention is indicated when severe obstruction has occurred. In this report, we describe the spontaneous regression of a large cardiac rhabdomyoma (20.5 × 15.6 mm) presenting as severe left ventricular inlet obstruction in a neonate with tuberous sclerosis. Although a cardiac rhabdomyoma can be large enough to induce left ventricular inlet obstruction, conservative treatment without aggressive surgical intervention can be considered if the hemodynamic condition does not deteriorate.

Serial evaluation of myocardial function using the myocardial performance index in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is known as systemic vasculitis, and more than half of the patients with KD have myocarditis, which can induce ventricular dysfunction. In this study, we evaluate left ventricular (LV) dysfunction in patients with KD based on the myocardial performance index (MPI) using pulse Doppler (PD) and tissue Doppler imaging (TDI), from the acute to convalescent phases. METHODS: We retrospectively studied 89 children diagnosed with KD from January 2010 to August 2012. We assessed the presence of coronary artery lesions (CALs) and the LV ejection fraction, PD-MPI, and TDI-MPI at diagnosis, and 2, 14, and 56 days after intravenous immunoglobulin (IVIG) treatment. We enrolled 70 healthy children as a control group. RESULTS: The ejection fraction in patients with KD at diagnosis (67.3 ± 0.9%) was lower than that in the control group (69.8 ± 0.8%, P = 0.035), and the LV TDI-MPIs for patients with KD at diagnosis (0.49 ± 0.01) and 2 days after IVIG treatment (0.48 ± 0.01) were higher than those in the control group (0.45 ± 0.01, P = 0.002, P = 0.033, respectively). No significant differences were found in the LV dysfunction between the patients with complete and incomplete KD. Septal TDI-MPIs in patients with KD with CAL at diagnosis (0.52 ± 0.02) were higher than those in patients with KD without CAL (0.47 ± 0.01, P = 0.019). CONCLUSIONS: Transient LV dysfunction occurred in patients with complete and incomplete KD in the acute stage. In patients with KD with CAL at diagnosis, the LV dysfunction was more prominent. The PD-MPI and TDI-MPI are useful parameters for assessing LV function in patients with KD.

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.