scholarly journals Roles and Targets of Class I and IIa Histone Deacetylases in Cardiac Hypertrophy

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Hae Jin Kee ◽  
Hyun Kook
Keyword(s):  
Cardiac Hypertrophy ◽  
Histone Deacetylases ◽  
Heart Diseases ◽  
Hdac Inhibitors ◽  
Underlying Mechanism ◽  
Class I ◽  
Inositol Polyphosphate ◽  
Stress Signals ◽  
Class I Hdacs ◽  
Class Iia Hdacs

Cardiac hypertrophy occurs in association with heart diseases and ultimately results in cardiac dysfunction and heart failure. Histone deacetylases (HDACs) are post-translational modifying enzymes that can deacetylate histones and non-histone proteins. Research with HDAC inhibitors has provided evidence that the class I HDACs are pro-hypertrophic. Among the class I HDACs, HDAC2 is activated by hypertrophic stresses in association with the induction of heat shock protein 70. Activated HDAC2 triggers hypertrophy by inhibiting the signal cascades of either Krüppel like factor 4 (KLF4) or inositol polyphosphate-5-phosphatase f (Inpp5f). Thus, modulators of HDAC2 enzymes, such as selective HDAC inhibitors, are considered to be an important target for heart diseases, especially for preventing cardiac hypertrophy. In contrast, class IIa HDACs have been shown to repress cardiac hypertrophy by inhibiting cardiac-specific transcription factors such as myocyte enhancer factor 2 (MEF2), GATA4, and NFAT in the heart. Studies of class IIa HDACs have shown that the underlying mechanism is regulated by nucleo-cytoplasm shuttling in response to a variety of stress signals. In this review, we focus on the class I and IIa HDACs that play critical roles in mediating cardiac hypertrophy and discuss the non-histone targets of HDACs in heart disease.

scholarly journals Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

2020 ◽  
Vol 21 (22) ◽  
pp. 8828
Author(s):  
Yuxiang Luo ◽  
Huilin Li
Keyword(s):  
Side Effects ◽  
Histone Deacetylases ◽  
Neurological Diseases ◽  
Hdac Inhibitors ◽  
Class I ◽  
Inhibitor Discovery ◽  
Isoform Selectivity ◽  
Class I Hdacs ◽  
Insight Into ◽  
Specific Inhibitors

Class I histone deacetylases (HDACs) are promising targets for epigenetic therapies for a range of diseases such as cancers, inflammations, infections and neurological diseases. Although six HDAC inhibitors are now licensed for clinical treatments, they are all pan-inhibitors with little or no HDAC isoform selectivity, exhibiting undesirable side effects. A major issue with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Except for HDAC8, Class I HDACs (1, 2 and 3) are recruited to large multiprotein complexes to function. Therefore, there are rising needs to develop new, hopefully, therapeutically efficacious HDAC inhibitors with isoform or complex selectivity. Here, upon the introduction of the structures of Class I HDACs and their complexes, we provide an up-to-date overview of the structure-based discovery of Class I HDAC inhibitors, including pan-, isoform-selective and complex-specific inhibitors, aiming to provide an insight into the discovery of additional HDAC inhibitors with greater selectivity, specificity and therapeutic utility.

scholarly journals Regulation of Mammalian Epithelial Differentiation and Intestine Development by Class I Histone Deacetylases

2004 ◽  
Vol 24 (8) ◽  
pp. 3132-3139 ◽  
Author(s):  
Liqiang Tou ◽  
Qiang Liu ◽  
Ramesh A. Shivdasani
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Class I ◽  
Specific Gene ◽  
Gene Promoters ◽  
Vertebrate Development ◽  
Control Of Gene Expression ◽  
Mouse Intestine ◽  
Class I Hdacs

ABSTRACT The biochemical mechanisms underlying epigenetic control of gene expression are increasingly well known. In contrast, the contributions of individual modifications toward activation of lineage-specific genes during vertebrate development are poorly understood. Class II histone deacetylases (HDACs), which show restricted tissue distribution, regulate muscle-specific gene expression, in part through interactions with myogenic transcription factors. We have combined gene expression profiling with manipulation of fetal mouse intestinal tissue to define roles for other regulatory factors. We found that in the developing mouse intestine class I HDACs are confined to the prospective epithelium and that their levels decline coincidently with activation of differentiation genes, suggesting a functional relationship between these events. Overexpression of wild-type but not of mutant HDACs 1 and 2 in fetal intestine explants reverses expression of certain maturation markers. HDAC inhibitors, including the selective class I antagonist valproic acid, activate the same genes prematurely and accelerate cytodifferentiation. Chromatin immunoprecipitation of freshly isolated organs reveals early HDAC2 occupancy at differentiation gene promoters and corresponding histone hypoacetylation that reverses as HDAC levels fall. Thus, modulation of endogenous class I HDAC levels represents a previously unappreciated mechanism to enable onset of tissue-restricted gene expression in a developing mammalian organ.

Abstract 238: Class I HDAC inhibition prevents Ncx1 upregulation by stabilizing an HDAC5-HDAC1/Sin3a Repressor Complex during cardiac hypertrophy.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sabina Wang ◽  
Lillianne G Harris ◽  
Santhosh Mani ◽  
Donald Menick
Keyword(s):  
Cardiac Hypertrophy ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Class I ◽  
Proximal Promoter ◽  
Hdac Inhibition ◽  
Repressor Complex

Cardiac hypertrophy is often associated with the activation of signaling pathways that perpetuate altered calcium efflux and influx. One gene that is upregulated and contributes to altered intracellular calcium concentrations and worsening contractility during cardiac hypertrophy is the Sodium Calcium Exchanger ( Ncx1 ). Molecular studies implicate histone deacetylases (HDACs) in possibly regulating the expression of this gene. Our recent work reveals that HDAC1, HDAC5 and Sin3a interact and are recruited to the Ncx1 promoter through the Nkx2.5 transcription factor. Interestingly, we observed greater associated/interaction of the HDAC1-HDAC5/Sin3a repressor complex upon broad HDAC inhibition. Taken together, we hypothesized that HDAC inhibition, stabilizes an HDAC1-HDAC5/Sin3a repressor complex during cardiac hypertrophy. We addressed this hypothesis by treating isolated adult cardiomyocytes with class specific HDAC inhibitors since HDAC1 is a Class I HDAC and HDAC5 is a Class IIa HDAC. Co-Immunoprecipitation (Co-IP) revealed a greater association of repressor complex molecules in the presence of Entinostat, a Class I HDAC inhibitor compared to both non-treated control and TSA, a broad HDAC inhibitor (n=3). These works show enhanced recruitment Sin3a (co-repressor) at the proximal promoter of NCX1 as demonstrated by Chromatin-Immunoprecipitation (ChIP) (n=3). To test whether these observations translated into in vivo models, we subjected mice to transaortic constriction (TAC) to induce hypertrophy. In this model, Co-IP revealed results that similar to our in vitro studies with greater immuno- detection of repressor complex component, Sin3a after immune-precipitation with HDAC1. Furthermore, our ChIP data showed a greater PCR product amplification of proximal Ncx1 promoter, from experimental groups that were subjected to Entinostat (n=3). Our cumulative data suggests that Class I HDAC inhibition stabilizes a repressor complex on the Ncx1 promoter that hinders hypertrophy- mediated Ncx1 upregulation. Class specific HDAC inhibition may be useful in the stabilization and repression of aberrantly expressed genes that contribute to poor clinical outcomes in cardiac hypertrophy.

Abstract 236: HDAC5 is Required for Recruitment of an HDAC1/Sin3a Repressor Complex to the Ncx1 Promoter During Cardiac Hypertrophy

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Lillianne G Harris ◽  
Sabina Wang ◽  
Santhosh K Mani ◽  
Harinath Kasiganesan ◽  
Donald K Menick
Keyword(s):  
Gene Expression ◽  
Catalytic Activity ◽  
Cardiac Hypertrophy ◽  
Hdac Inhibitor ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Class I ◽  
Adult Cardiomyocytes ◽  
Student’S T ◽  
Class Iia Hdacs

Background: Pressure overload can lead to aberrant gene expression and subsequent adverse hypertrophic changes in cardiac tissue. Histone deacetylases (HDACs) play an important role in alteration of gene expression during cardiac hypertrophy. We observed that class I/IIb HDAC inhibitors, TSA and Vorinostat prevent upregulation of the sodium calcium exchanger gene, Ncx1 , in response to cardiac hypertrophy. Chromatin immunoprecipitation (ChIP) demonstrates the class I HDAC, HDAC1, class IIa HDAC, HDAC5 and co-repressor, Sin3a are recruited to the Ncx1 promoter via Nkx2.5. Class IIa HDACs have very poor catalytic activity and can interact with many specific transcription factors. Thus, we hypothesized , that the class IIa, HDAC5 acts as a scaffold to recruit the class I HDAC/Sin3a complex to the Ncx1 promoter. Methods and Results: To test our hypothesis adult cardiomyocytes were treated with either vehicle (control) or class specific HDAC inhibitors: class I (Entinostat), or class IIa (dPAHA). We found that class I HDAC inhibitor, Entinostat, abrogates adrenergic stimulated upregulation of Ncx1 expression in adult cardiomyocytes to almost control levels (p<0.05 Student’s t; n=4), while class IIa HDAC inhibitor, dPAHA has no effect on adrenergic stimulated upregulation of Ncx1 expression (p>0.05 Student’s t; n=4). Also, Entinostat inhibits Ncx1 upregulation in a transaortic constriction (TAC) model of hypertrophy. We assessed the role class IIa HDAC5 in Ncx1 regulation, by subjecting HDAC5-Knockout mice (HDAC5-KO) to TAC. We saw no induction of Ncx1 expression post-TAC (n=5). Furthermore, Co-IP and ChIP analyses show that interactions between the Sin3a/HDAC1 complex and Nkx2.5 are lost in the absence of HDAC5 expression and fail to be recruited to the Ncx1 promoter. To conclude , our data suggests the catalytic activity of HDAC5 is not essential but rather HDAC5 is a scaffold that recruits the class I HDAC1–Sin3a complex to the Ncx1 promoter. Our novel findings provide insight into possible roles of class IIa HDACs in regulation of gene expression and efficacy of HDAC inhibitors to treat cardiac pathologies.

scholarly journals Selective inhibition of HDAC2 by magnesium valproate attenuates cardiac hypertrophy

2017 ◽  
Vol 95 (3) ◽  
pp. 260-267 ◽  
Author(s):  
Suchi Raghunathan ◽  
Ramesh K. Goyal ◽  
Bhoomika M. Patel
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Cardiac Hypertrophy ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Selective Inhibition ◽  
Class Ii ◽  
Class I ◽  
Hdac Inhibition ◽  
Dna Concentration

The regulatory paradigm in cardiac hypertrophy involves alterations in gene expression that is mediated by chromatin remodeling. Various data suggest that class I and class II histone deacetylases (HDACs) play opposing roles in the regulation of hypertrophic pathways. To address this, we tested the effect of magnesium valproate (MgV), an HDAC inhibitor with 5 times more potency on class I HDACs. Cardiac hypertrophy was induced by partial abdominal aortic constriction in Wistar rats, and at the end of 6 weeks, we evaluated hypertrophic, hemodynamic, and oxidative stress parameters, and mitochondrial DNA concentration. Treatment with MgV prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress, and increased mitochondrial DNA concentration. MgV treatment also increased the survival rate of the animals as depicted by the Kaplan–Meier curve. Improvement in hypertrophy due to HDAC inhibition was further confirmed by HDAC mRNA expression studies, which revealed that MgV decreases expression of pro-hypertrophic HDAC (i.e., HDAC2) without altering the expression of anti-hypertrophic HDAC5. Selective class I HDAC inhibition is required for controlling cardiac hypertrophy. Newer HDAC inhibitors that are class I inhibitors and class II promoters can be designed to obtain “pan” or “dual” natural HDAC “regulators”.

scholarly journals Functional Interaction between Class II Histone Deacetylases and ICP0 of Herpes Simplex Virus Type 1

2004 ◽  
Vol 78 (13) ◽  
pp. 6744-6757 ◽  
Author(s):  
Patrick Lomonte ◽  
Joëlle Thomas ◽  
Pascale Texier ◽  
Cécile Caron ◽  
Saadi Khochbin ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Histone Deacetylases ◽  
Class Ii ◽  
Class I ◽  
Transfected Cells ◽  
Amino Terminal ◽  
Simplex Virus ◽  
Class I Hdacs

ABSTRACT This study describes the physical and functional interactions between ICP0 of herpes simplex virus type 1 and class II histone deacetylases (HDACs) 4, 5, and 7. Class II HDACs are mainly known for their participation in the control of cell differentiation through the regulation of the activity of the transcription factor MEF2 (myocyte enhancer factor 2), implicated in muscle development and neuronal survival. Immunofluorescence experiments performed on transfected cells showed that ICP0 colocalizes with and reorganizes the nuclear distribution of ectopically expressed class I and II HDACs. In addition, endogenous HDAC4 and at least one of its binding partners, the corepressor protein SMRT (for silencing mediator of retinoid and thyroid receptor), undergo changes in their nuclear distribution in ICP0-transfected cells. As a result, during infection endogenous HDAC4 colocalizes with ICP0. Coimmunoprecipitation and glutathione S-transferase pull-down assays confirmed that class II but not class I HDACs specifically interacted with ICP0 through their amino-terminal regions. This region, which is not conserved in class I HDACs but homologous to the MITR (MEF2-interacting transcription repressor) protein, is responsible for the repression, in a deacetylase-independent manner, of MEF2 by sequestering it under an inactive form in the nucleus. Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays. This is the first report of a viral protein interacting with and controlling the repressor activity of class II HDACs. We discuss the putative consequences of such an interaction for the biology of the virus both during lytic infection and reactivation from latency.

Abstract 239: Selective Class I and II Histone Deacetylation Inhibitors Alter Stability of HDAC-Corepressor Complexes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Hsiao C Wang ◽  
Lillianne G Harris ◽  
James C Chou ◽  
Santhosh Mani ◽  
Donald Menick
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Hdac Inhibitors ◽  
Class I ◽  
Proximal Promoter ◽  
Repressor Complex ◽  
The Stability

Introduction: Alterations in expression and activity of different genes have been implicated in the pathogenesis of heart failure. Our lab has shown that HDAC-repressor complexes play a critical role in the upregulation Sodium Calcium Exchanger ( Ncx1) and HDAC inhibition causes changes that attenuated cardiac remodeling during cardiac hypertrophy and heart failure. Thus, treatment with HDAC inhibitors has been proposed as a potential strategy for treatment of cardiac hypertrophy and heart failure. HDAC inhibitors repress deacetylase activity but we propose that they also affect HDAC confirmation and interaction with other protein factors. We hypothesize that HDAC inhibitors affect the stability of the co-repressor complex with specific transcription factors and that this effect is dependent on the transcription factor. Results: Inhibition of HDACs in adult cardiomyocytes results in the greater stabilization of HDACs with co-repressor molecules that were recruited to the NCX1 promoter through Nkx2.5 transcription factor. HDAC class I specific inhibitor, MS 275 demonstrated stronger association between HDACs and co-repressors while other Class I inhibitors, PD106 and BML 210 failed on showing this phenomenal. The results suggested that class I HDACs inhibitors may affect formations of HDAC-complex via alternated active site interactions other than chelating with zinc binding domain. These results compliment ChIP experiments which also demonstrate the different recruitments of Sin3a at the proximal promoter of NCX1. In vivo analysis on HDAC5 knockout mice reveal that the Sin3a-HDAC1/2 repressor complex is not recruited to the Ncx1 promoter in the absence of HDAC5, indicating not only Class I HDAC but also Class II HDACs play an important role on HDAC-complex formation. Conclusions: This work gives insight into part of the molecular mechanism of how HDAC inhibitors can affect the stability of the HDAC co-repressor complex in cardiac hypertrophy and heart failure. In addition, we demonstrated the Class IIa HDACs are required for the recruitment of the Sin3a/HDAC1/2 co-repressor complex to specific transcription factors on the target promoter.

Abstract 310: Inhibition of Class I Histone Deacetylase Activity Improves Left Ventricular Contractile Function and Cardiac Strain in Coronary Artery Occlusion-Induced Myocardial Infarction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Harinath Kasiganesan ◽  
Ludivine Renaud ◽  
Santhosh K Mani ◽  
Chou C James ◽  
Rupak Mukherjee ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Histone Deacetylases ◽  
Contractile Function ◽  
Strain Analysis ◽  
Left Ventricular ◽  
Class I ◽  
Border Zones ◽  
Cardiac Strain ◽  
Class I Hdacs

Protection from coronary heart disease-induced damage of the myocardium during myocardial infarction (MI) injury has been a target of investigation for the development of innovative cardioprotective therapies. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We observed that class I/IIb HDAC activity was nearly 5 times greater in the 7-day post-MI LV when compared to the sham ventricles. In vitro inhibition studies indicated that the majority of increased activity was due to class I HDACs. Therefore we hypothesized that suppression of class I HDACs would prevent the pathophysiological changes occurring during MI, thus improving LV pump function in post-MI myocardium. CD-1 mice were administered with the a class I HDAC inhibitor pimelic diphenylamide (PD106) or vehicle immediately after induction of MI and the treatment continued every other day for 7 days post MI. LV end-diastolic volumes, expressed as change from pre-MI values, was significantly lower in the PD106 treated mice compared to vehicle treated mice. Further, the post-MI reduction in LV ejection faction was significantly attenuated in the PD106-treated mice compared to the MI alone group. Similarly, echo cardiac strain analysis showed improved LV strain and better coherence in contractile function among infarct and border zones in PD106 MI group compared to MI only. These unique findings demonstrate that class I HDAC inhibitors may provide a novel therapeutic means to attenuate adverse post-MI LV remodeling.

scholarly journals Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma

2020 ◽  
Author(s):  
Jonas Ecker ◽  
Venu Thatikonda ◽  
Gianluca Sigismondo ◽  
Florian Selt ◽  
Gintvile Valinciute ◽  
...  
Keyword(s):  
Molecular Interaction ◽  
Hdac Inhibitors ◽  
Class I ◽  
Chromatin Binding ◽  
Hdac Inhibition ◽  
Primary Tumors ◽  
Chip Sequencing ◽  
Class I Hdacs ◽  
The Impact ◽  
Selection Of

Abstract Background The sensitivity of myelocytomatosis oncogene (MYC) amplified medulloblastoma to class I histone deacetylase (HDAC) inhibition has been shown previously; however, understanding the underlying molecular mechanism is crucial for selection of effective HDAC inhibitors for clinical use. The aim of this study was to investigate the direct molecular interaction of MYC and class I HDAC2, and the impact of class I HDAC inhibition on MYC function. Methods Co-immunoprecipitation and mass spectrometry were used to determine the co-localization of MYC and HDAC2. Chromatin immunoprecipitation (ChIP) sequencing and gene expression profiling were used to analyze the co-localization of MYC and HDAC2 on DNA and the impact on transcriptional activity in primary tumors and a MYC amplified cell line treated with the class I HDAC inhibitor entinostat. The effect on MYC was investigated by quantitative real-time PCR, western blot, and immunofluorescence. Results HDAC2 is a cofactor of MYC in MYC amplified medulloblastoma. The MYC-HDAC2 complex is bound to genes defining the MYC-dependent transcriptional profile. Class I HDAC inhibition leads to stabilization and reduced DNA binding of MYC protein, inducing a downregulation of MYC activated genes (MAGs) and upregulation of MYC repressed genes (MRGs). MAGs and MRGs are characterized by opposing biological functions and by distinct enhancer-box distribution. Conclusions Our data elucidate the molecular interaction of MYC and HDAC2 and support a model in which inhibition of class I HDACs directly targets MYC’s transactivating and transrepressing functions.

Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases

2015 ◽  
Vol 75 (3) ◽  
pp. 593-600 ◽  
Author(s):  
Maartje C P Cleophas ◽  
Tania O Crişan ◽  
Heidi Lemmers ◽  
Helga Toenhake-Dijkstra ◽  
Gianluca Fossati ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Hdac Inhibitors ◽  
Class I ◽  
Acute Gout ◽  
Monosodium Urate ◽  
Healthy Donors ◽  
Anti Inflammatory

ObjectivesAcute gouty arthritis is caused by endogenously formed monosodium urate (MSU) crystals, which are potent activators of the NLRP3 inflammasome. However, to induce the release of active interleukin (IL)-1β, an additional stimulus is needed. Saturated long-chain free fatty acids (FFAs) can provide such a signal and stimulate transcription of pro-IL-1β. In contrast, the short-chain fatty acid butyrate possesses anti-inflammatory effects. One of the mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU+FFA-induced cytokine production and its inhibition of specific HDACs.MethodsFreshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or a synthetic HDAC inhibitor. Cytokine responses were measured with ELISA and quantitative PCR. HDAC activity was measured with fluorimetric assays.ResultsButyrate decreased C16.0+MSU-induced production of IL-1β, IL-6, IL-8 and IL-1β mRNA in PBMCs from healthy donors. Similar results were obtained in PBMCs isolated from patients with gout. Butyrate specifically inhibited class I HDACs. The HDAC inhibitor, panobinostat and the potent HDAC inhibitor, ITF-B, also decreased ex vivo C16.0+MSU-induced IL-1β production.ConclusionsIn agreement with the reported low inhibitory potency of butyrate, a high concentration was needed for cytokine suppression, whereas synthetic HDAC inhibitors showed potent anti-inflammatory effects at nanomolar concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.

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