A cardiac microRNA governs systemic energy homeostasis by regulation of MED13.

Obesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders.

Icariin alleviates ferroptosis-related atherosclerosis by promoting autophagy in xo-LDL-induced vascular endothelial cell injury and atherosclerotic mice.

Vascular endothelial cells (VECs) are located between the blood plasma and the vascular tissue, and the ferroptosis (iron-dependent programmed cell death) of VECs can lead to a range of cardiovascular diseases. Icariin is the main active ingredient of Epimedium brevicornum Maxim., which can improve endothelial cell dysfunction. In the present study, the protective effects of icariin on oxidised low-density lipoprotein (ox-LDL)-treated VECs and high-fat diet-fed Apolipoprotein E-deficient mice were investigated. Inflammatory fibrosis in tissues and inflammatory factors in serum and cell supernatants were detected, and mitochondrial membrane potential and the expression levels of ferroptosis-associated proteins were also detected. The results revealed that icariin reduced the endothelial atherosclerotic plaque area and collagen fibres in aortic sinus tissue, and increased the viability and mitochondrial membrane potential, whereas it reduced the reactive oxygen species levels of VECs. The nucleation of transcription factor EB (TFEB) and subsequent autophagy were negatively associated with ferroptosis in endothelial cells, and the more prominent the autophagy, the lower the levels of ferroptosis. Furthermore, by co-treating the cells with icariin and the two autophagy inhibitors, Bafilomycin A1 (blocking autophagosome and lysosome fusion) and 3-methyladenine (blocking autophagosome formation), respectively, the promoting effects of icariin on autophagy were found to be mediated through the process of autophagosome-lysosome fusion. In in vivo experiments, icariin reduced ferroptosis, alleviated atherosclerotic lesions and increased the rate of TFEB nucleation. Additionally, it was found that ARG304, THR308 and GLN311 were the optimal binding sites for the interaction between icariin and TFEB. Taken together, these results suggest that the fusion of autophagosomes and lysosomes promoted by icarrin enhances autophagy and thus reduces ferroptosis. Therefore, icariin may be a potential candidate for the prevention of ferroptosis of VECs and, thus, for the treatment of cardiovascular diseases.

Effects of Kuntai capsule on breast pain and vaginal bleeding in postmenopausal women.

Aim of the present work was to investigate the clinical efficacy of Kuntai capsule in the treatment of postmenopausal women with endometriosis, Breast pain and Vaginal Bleeding. 120 elderly female outpatients over 50 years old with Breast pain were randomly divided into control group (60 cases) and observation group (60 cases). All patients were given diclofenac sodium enteric-coated tablets 25mg, 3 times a day. The observation group was given additional Kuntai capsules at a dose of 4 capsules per time, 3 times a day. Serum estradiol (E2), follicle stimulating hormone (FSH), and luteinizing hormone (LH) were detected in all patients before and at 12 weeks after treatment. Modified Kupperman score (K score) for evaluating menopausal symptoms. The post therapeutic serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) level and endometrial thickness decreased significantly (p<0.05). After treatment, KMI scores of kunati group was significantly decreased compared with baseline (<0.01) and there was no significant difference between groups (p>0.05). After treatment, hot flush and insomnia scores were both improved significantly. After therapy, serum E2 level obviously higher than the control groups, while FSH and LH levels were obviously lower (p<0.05). The incidence of vaginal bleeding, breast distending pain in group was obviously higher in control group than Kuntai group. Thus, Kuntai capsule improved the ovarian function of patients, raised the level of estrogen in vivo and alleviates the clinical manifestations of Breast pain.

Heart repair by reprogramming non-myocytes with cardiac transcription factors.

The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, HAND2, MEF2C and TBX5, can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.

Targeted salinomycin delivery with EGFR and CD133 aptamers based dual-ligand lipid-polymer nanoparticles to both osteosarcoma cells and cancer stem cells.

We previously developed salinomycin (sali)-entrapped nanoparticles labeled with CD133 aptamers which could efficiently eliminate CD133+ osteosarcoma cancer stem cells (CSCs). However, sufficient evidences suggest that the simultaneous targeting both CSCs and cancer cells is pivotal in achieving preferable cancer therapeutic efficacy, due to the spontaneous conversion between cancer cells and CSCs. We hereby constructed sali-entrapped lipid-polymer nanoparticles labeled with CD133 and EGFR aptamers (CESP) to target both osteosarcoma cells and CSCs. The cytotoxicity of CESP in osteosarcoma cells and CSCs was superior to that of single targeting or nontargeted sali-loaded nanoparticles. Administration of CESP in vivo showed the best efficacy in inhibiting tumor growth than other controls in osteosarcoma-bearing mice. Thus, CESP was demonstrated to be capable of efficiently targeting both osteosarcoma CSCs and cancer cells, and it represents an effective potential approach to treat osteosarcoma.

Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3zeta.

Erythrocyte formation occurs throughout life in response to cytokine signaling. We show that microRNA-451 (miR-451) regulates erythropoiesis in vivo. Mice lacking miR-451 display a reduction in hematrocrit, an erythroid differentiation defect, and ineffective erythropoiesis in response to oxidative stress. 14-3-3zeta, an intracellular regulator of cytokine signaling that is repressed by miR-451, is up-regulated in miR-451(-/-) erythroblasts, and inhibition of 14-3-3zeta rescues their differentiation defect. These findings reveal an essential role of 14-3-3zeta as a mediator of the proerythroid differentiation actions of miR-451, and highlight the therapeutic potential of miR-451 inhibitors.

Ataxia and Purkinje cell degeneration in mice lacking the CAMTA1 transcription factor.

Members of the calmodulin-binding transcription activator (CAMTA) family of proteins function as calcium-sensitive regulators of gene expression in multicellular organisms ranging from plants to humans. Here, we show that global or nervous system deletion of CAMTA1 in mice causes severe ataxia with Purkinje cell degeneration and cerebellar atrophy, partially resembling the consequences of haploinsufficiency of the human CAMTA1 locus. Gene-expression analysis identified a large collection of neuronal genes that were dysregulated in the brains of CAMTA1-mutant mice, and elucidation of a consensus sequence for binding of CAMTA proteins to DNA revealed the association of CAMTA-binding sites with many of these genes. We conclude that CAMTA1 plays an essential role in the control of Purkinje cell function and survival. CAMTA1-mutant mice provide a model to study the molecular mechanisms of neurodegenerative diseases and for screening potential therapeutic interventions for such disorders.

MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury.

Vascular injury triggers dedifferentiation and cytoskeletal remodeling of smooth muscle cells (SMCs), culminating in vessel occlusion. Serum response factor (SRF) and its coactivator, myocardin, play a central role in the control of smooth muscle phenotypes by regulating the expression of cytoskeletal genes. We show that SRF and myocardin regulate a cardiovascular-specific microRNA (miRNA) cluster encoding miR-143 and miR-145. To assess the functions of these miRNAs in vivo, we systematically deleted them singly and in combination in mice. Mice lacking both miR-143 and miR-145 are viable and do not display overt abnormalities in smooth muscle differentiation, although they show a significant reduction in blood pressure due to reduced vascular tone. Remarkably, however, neointima formation in response to vascular injury is profoundly impeded in mice lacking these miRNAs, due to disarray of actin stress fibers and diminished migratory activity of SMCs. These abnormalities reflect the regulation of a cadre of modulators of SRF activity and actin dynamics by miR-143 and miR-145. Thus, miR-143 and miR-145 act as integral components of the regulatory network whereby SRF controls cytoskeletal remodeling and phenotypic switching of SMCs during vascular disease.

[Huangqi Danshen decoction attenuates isoproterenol-induced myocardial remodeling via STIM1, TRPC1, CaN and NFATc3 pathways in rats].

To investigate the inhibitory effect of Huangqi Danshen decoction (HDD) on isoproterenol (ISO)-induced myocardial remodeling and explore its effect on STIM1, TRPC1, CaN and NFATc3 expressions. ISO (2.5 mg•kg⁻¹â€¢d⁻¹×14 d) was given by subcutaneous injection to establish myocardial remodeling models in rats, and then were randomly divided into control group, ISO model group, HDD5 group (HDD 5 g•kg⁻¹â€¢d⁻¹+ISO), and HDD10 group (HDD 10 g•kg⁻¹â€¢d⁻¹+ISO). After intervention for 4 weeks, the heart mass index (HW/BW) and the left ventricular mass index (LVW/BW) were calculated; the structure of myocardium was observed by echocardiography; the pathological changes of myocardium were observed by HE staining; levels of BNP, CaN and CaM kinases II in serum were detected by ELISA, and the protein expression levels of STIM1, TRPC1, p-CaN, p-NFATc3, and NFATc3 in left ventricular tissues were detected by Western blot. The results showed that the HW/BW and LVW/BW in ISO group were greater than those in HDD5 group and HDD10 group (P<0.05); Echocardiography showed that HDD inhibited ISO-induced increase in LVEDD and LVESD; ELISA results showed that HDD could significantly inhibit the increase of BNP, CaN and CaM kinases II levels in serum of rats with ISO-induced myocardial remodeling (P<0.01). Western blot results showed that STIM1, TRPC1, p-CaN, p-NFATc3 and NFATc3 expression levels were increased in the myocardial tissues of ISO group rats, and after HDD administration, the above expression levels were decreased in group ISO, HDD for myocardial tissue after administration of STIM1, TRPC1, p-CaN, p-NFATc3 and NFATc3 expression decreased (P<0.05). Our findings indicated that HDD can attenuate the myocardial remodeling induced by ISO, and its mechanism may be related to down-regulating the expression levels of STIM1, TRPC1, CaM kinases II, p-CaN/CaN and p-NFATc3/NFATc3.

Hippo pathway effector Yap promotes cardiac regeneration.

The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.

Roles of NAD in Protection of Axon against Degeneration via SIRT1 Pathways.

Axonal degeneration is a common pathological change of neurogenical disease which often arises before the neuron death. But it had not found any effective method to protect axon from degeneration. In this study we intended to confirm the protective effect of nicotinamide adenine dinucleotide (NAD), investigate the optimal administration dosage and time of NAD, and identify the relationship between silence signal regulating factor 1 (SIRT1) and axonal degeneration. An axonal degeneration model was established using dorsal root ganglion (DRG) neurons injured by vincristine to observe the protective effects of NAD to the injured axons. In addition, the potential contribution of the SIRT1 in axonal degeneration was also investigated. Through the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunochemistry staining, axons counting and length measuring, transmission electron microscope (TEM) observation, we demonstrated that NAD played an important role in preventing axonal degeneration. Further study revealed that the expression of SIRT1 and phosphorylated Akt1 (p-Akt1) was up-regulated when NAD was added into the culturing medium. Taking together, our results demonstrated that NAD might delay the axonal degeneration through SIRT1/Akt1 pathways.

A case report of successful rescue using veno-arterial extracorporeal membrane oxygenation: managing cerebral-cardiac syndrome.

Introduction: The presence of cerebral-cardiac syndrome, wherein brain diseases coincide with heart dysfunction, significantly impacts patient prognosis. In severe instances, circulatory failure may ensue, posing a life-threatening scenario necessitating immediate life support measures, particularly effective circulatory support methods. The application of extracorporeal membrane oxygenation (ECMO) is extensively employed as a valuable modality for delivering circulatory and respiratory support in the care of individuals experiencing life-threatening circulatory and respiratory failure. This approach facilitates a critical temporal window for subsequent interventions. Consequently, ECMO has emerged as a potentially effective life support modality for patients experiencing severe circulatory failure in the context of cerebral-cardiac syndrome. However, the existing literature on this field of study remains limited. Case description: In this paper, we present a case study of a patient experiencing a critical cerebral-cardiac syndrome. The individual successfully underwent veno-arterial-ECMO (VA-ECMO) therapy, and the patient not only survived, but also received rehabilitation treatment, demonstrating its efficacy as a life support intervention. Conclusion: VA-ECMO could potentially serve as an efficacious life support modality for individuals experiencing severe circulatory failure attributable to cerebral-cardiac syndrome.

Case Report: Resuscitation of patient with tumor-induced acute pulmonary embolism by venoarterial extracorporeal membrane oxygenation.

Background: Pulmonary embolism is a condition of right cardiac dysfunction due to pulmonary circulation obstruction. Malignant tumor-induced pulmonary embolism, which has a poor therapeutic outcome and a significant impact on hemodynamics, is the cause of sudden death in patients with malignant tumors. Case description: A 38-year-old female patient, who had a medical history of right renal hamartoma, and right renal space-occupying lesion, was admitted to the hospital. During the procedure to resect the right renal malignancy, the blood pressure and end-tidal carbon dioxide level dropped, and a potential pulmonary embolism was considered as a possibility. After inferior vena cava embolectomy, the hemodynamics in the patient remained unstable. The successful establishment of venoarterial extracorporeal membrane oxygenation (VA-ECMO) resulted in the stabilization of her hemodynamics and ventilation. On Day 2 of VA-ECMO support, her respiration and hemodynamics were relatively stable, and ECMO assistance was successfully terminated following the "pump-controlled retrograde trial off (PCRTO)" test on Day 6. The patient improved gradually after the procedure and was discharged from the hospital after 22 days. Conclusion: VA-ECMO can be used as a transitional resuscitation technique for patients with massive pulmonary embolism. It is critical for the perfusion of vital organs and can assist with surgical or interventional treatment, lower right heart pressure, and hemodynamic stability. VA-ECMO has a significant impact on patient prognosis and can reduce the mortality rate.

The gamma isoform of CaM kinase II controls mouse egg activation by regulating cell cycle resumption.

Fertilization triggers a rise in intracellular Ca(2+) concentration ([Ca(2+)](i)) in the egg that initiates a series of events known as egg activation. These events include cortical granule exocytosis that establishes a block to polyspermy, resumption of meiosis, and recruitment of maternal mRNAs into polysomes for translation. Several calcium-dependent proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII), have been implicated in egg activation. However, the precise role of CaMKII in mediating specific events of egg activation and the identity of the isoform(s) present in mouse eggs have not been unequivocally established. Through targeted deletion of the gamma isoform of CaMKII, we find that CaMKIIgamma is the predominant CaMKII isoform in mouse eggs and that it is essential for egg activation. Although CaMKIIgamma(-/-) eggs exhibit a normal pattern of Ca(2+) oscillations after insemination and undergo cortical granule exocytosis, they fail to resume meiosis or to recruit maternal mRNAs. Surprisingly, we find that the recruitment of maternal mRNAs does not directly depend on CaMKII, but requires elevated [Ca(2+)](i) and metaphase II exit. We conclude that CaMKIIgamma specifically controls mouse egg activation by regulating cell cycle resumption.

MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs.

Piwi-interacting RNAs (piRNAs) comprise a broad class of small noncoding RNAs that function as an endogenous defense system against transposable elements. Here we show that the putative DExD-box helicase MOV10-like-1 (MOV10L1) is essential for silencing retrotransposons in the mouse male germline. Mov10l1 is specifically expressed in germ cells with increasing expression from gonocytes/type A spermatogonia to pachytene spermatocytes. Primary spermatocytes of Mov10l1(-/-) mice show activation of LTR and LINE-1 retrotransposons, followed by cell death, causing male infertility and a complete block of spermatogenesis at early prophase of meiosis I. Despite the early expression of Mov10l1, germline stem cell maintenance appears unaffected in Mov10l1(-/-) mice. MOV10L1 interacts with the Piwi proteins MILI and MIWI. MOV10L1 also interacts with heat shock 70-kDa protein 2 (HSPA2), a testis-enriched chaperone expressed in pachytene spermatocytes and also essential for male fertility. These studies reveal a crucial role of MOV10L1 in male fertility and piRNA-directed retrotransposon silencing in male germ cells and suggest that MOV10L1 functions as a key component of a safeguard mechanism for the genetic information in male germ cells of mammals.

MEF2C transcription factor controls chondrocyte hypertrophy and bone development.

Chondrocyte hypertrophy is essential for endochondral bone development. Unexpectedly, we discovered that MEF2C, a transcription factor that regulates muscle and cardiovascular development, controls bone development by activating the gene program for chondrocyte hypertrophy. Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice. Conversely, a superactivating form of MEF2C causes precocious chondrocyte hypertrophy, ossification of growth plates, and dwarfism. Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4), such that bone deficiency of Mef2c mutant mice can be rescued by an Hdac4 mutation, and ectopic ossification in Hdac4 null mice can be diminished by a heterozygous Mef2c mutation. These findings reveal unexpected commonalities in the mechanisms governing muscle, cardiovascular, and bone development with respect to their regulation by MEF2 and class II HDACs.

Regulation of atrial natriuretic peptide secretion by a novel Ras-like protein.

Atrial cardiomyocytes, neurons, and endocrine tissues secrete neurotransmitters and peptide hormones via large dense-core vesicles (LDCVs). We describe a new member of the Ras family of G-proteins, named RRP17, which is expressed specifically in cardiomyocytes, neurons, and the pancreas. RRP17 interacts with Ca(2+)-activated protein for secretion-1 (CAPS1), one of only a few proteins known to be associated exclusively with LDCV exocytosis. Ectopic expression of RRP17 in cardiomyocytes enhances secretion of atrial natriuretic peptide (ANP), a regulator of blood pressure and natriuresis. Conversely, genetic deletion of RRP17 in mice results in dysmorphic LDCVs, impaired ANP secretion, and hypertension. These findings identify RRP17 as a component of the cellular machinery involved in regulated secretion within the heart and potential mediator of the endocrine influence of the heart on other tissues.

The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload.

Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads to pathological cardiac hypertrophy and remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transduction of calcium signals in the heart, but the specific isoforms of CaMKII that mediate pathological cardiac signaling have not been fully defined. To investigate the potential involvement in heart disease of CaMKIIdelta, the major CaMKII isoform expressed in the heart, we generated CaMKIIdelta-null mice. These mice are viable and display no overt abnormalities in cardiac structure or function in the absence of stress. However, pathological cardiac hypertrophy and remodeling are attenuated in response to pressure overload in these animals. Cardiac extracts from CaMKIIdelta-null mice showed diminished kinase activity toward histone deacetylase 4 (HDAC4), a substrate of stress-responsive protein kinases and suppressor of stress-dependent cardiac remodeling. In contrast, phosphorylation of the closely related HDAC5 was unaffected in hearts of CaMKIIdelta-null mice, underscoring the specificity of the CaMKIIdelta signaling pathway for HDAC4 phosphorylation. We conclude that CaMKIIdelta functions as an important transducer of stress stimuli involved in pathological cardiac remodeling in vivo, which is mediated, at least in part, by the phosphorylation of HDAC4. These findings point to CaMKIIdelta as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload.

The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice.

The adult heart responds to excessive neurohumoral signaling and workload by a pathological growth response characterized by hypertrophy of cardiomyocytes and activation of a fetal program of cardiac gene expression. These responses culminate in diminished pump function, ventricular dilatation, wall thinning, and fibrosis, and can result in sudden death. Myocyte enhancer factor-2 (MEF2) transcription factors serve as targets of the signaling pathways that drive pathological cardiac remodeling, but the requirement for MEF2 factors in the progression of heart disease in vivo has not been determined. MEF2A and MEF2D are the primary MEF2 factors expressed in the adult heart. To specifically determine the role of MEF2D in pathological cardiac remodeling, we generated mice with a conditional MEF2D allele. MEF2D-null mice were viable, but were resistant to cardiac hypertrophy, fetal gene activation, and fibrosis in response to pressure overload and beta-chronic adrenergic stimulation. Furthermore, we show in a transgenic mouse model that forced overexpression of MEF2D was sufficient to drive the fetal gene program and pathological remodeling of the heart. These results reveal a unique and important function for MEF2D in stress-dependent cardiac growth and reprogramming of gene expression in the adult heart.

Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice.

Histone deacetylase (HDAC) inhibitors show remarkable therapeutic potential for a variety of disorders, including cancer, neurological disease, and cardiac hypertrophy. However, the specific HDAC isoforms that mediate their actions are unclear, as are the physiological and pathological functions of individual HDACs in vivo. To explore the role of Hdac3 in the heart, we generated mice with a conditional Hdac3 null allele. Although global deletion of Hdac3 resulted in lethality by E9.5, mice with a cardiac-specific deletion of Hdac3 survived until 3-4 months of age. At this time, they showed massive cardiac hypertrophy and upregulation of genes associated with fatty acid uptake, fatty acid oxidation, and electron transport/oxidative phosphorylation accompanied by fatty acid-induced myocardial lipid accumulation and elevated triglyceride levels. These abnormalities in cardiac metabolism can be attributed to excessive activity of the nuclear receptor PPARalpha. The phenotype associated with cardiac-specific Hdac3 gene deletion differs from that of all other Hdac gene mutations. These findings reveal a unique role for Hdac3 in maintenance of cardiac function and regulation of myocardial energy metabolism.