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”.

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.

scholarly journals HDACs class II-selective inhibition alters nuclear receptor-dependent differentiation

2010 ◽  
Vol 45 (4) ◽  
pp. 219-228 ◽  
Author(s):  
Angela Nebbioso ◽  
Carmela Dell'Aversana ◽  
Anne Bugge ◽  
Roberta Sarno ◽  
Sergio Valente ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Selective Inhibition ◽  
Class Ii ◽  
Class I ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
F9 Cells ◽  
Anti Cancer ◽  
Cardiovascular Defects

Epigenetic deregulation contributes to diseases including cancer, neurodegeneration, osteodystrophy, cardiovascular defects, and obesity. For this reason, several inhibitors for histone deacetylases (HDACs) are being validated as novel anti-cancer drugs in clinical studies and display important anti-proliferative activities. While most inhibitors act on both class I, II, and IV HDACs, evidence is accumulating that class I is directly involved in regulation of cell growth and death, whereas class II members regulate differentiation processes, such as muscle and neuronal differentiation. Here, we show that the novel class II-selective inhibitor MC1568 interferes with the RAR- and peroxisome proliferator-activated receptor γ (PPARγ)-mediated differentiation-inducing signaling pathways. In F9 cells, this inhibitor specifically blocks endodermal differentiation despite not affecting retinoic acid-induced maturation of promyelocytic NB4 cells. In 3T3-L1 cells, MC1568 attenuates PPARγ-induced adipogenesis, while the class I-selective MS275 blocked adipogenesis completely thus revealing a different mode of action and/or target profile of the two classes of HDACs. Using in vivo reporting PPRE-Luc mice, we find that MC1568 impairs PPARγ signaling mostly in the heart and adipose tissues. These results illustrate how HDAC functions can be dissected by selective inhibitors.

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 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.

Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro

2011 ◽  
Vol 226 (12) ◽  
pp. 3233-3241 ◽  
Author(s):  
M.D. Cantley ◽  
D.P. Fairlie ◽  
P.M. Bartold ◽  
K.D. Rainsford ◽  
G.T. Le ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Class Ii ◽  
Class I ◽  
Human Osteoclasts

scholarly journals The Orphan Nuclear Receptor TR2 Interacts Directly with Both Class I and Class II Histone Deacetylases

2001 ◽  
Vol 15 (8) ◽  
pp. 1318-1328 ◽  
Author(s):  
Peter J. Franco ◽  
Mariya Farooqui ◽  
Edward Seto ◽  
Li-Na Wei
Keyword(s):  
Nuclear Receptor ◽  
Histone Deacetylases ◽  
Class Ii ◽  
Class I ◽  
Orphan Nuclear Receptor

scholarly journals Class I and Class II Histone Deacetylases Are Potential Therapeutic Targets for Treating Pancreatic Cancer

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e52095 ◽  
Author(s):  
Guan Wang ◽  
Jing He ◽  
Jianyun Zhao ◽  
Wenting Yun ◽  
Chengzhi Xie ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Histone Deacetylases ◽  
Therapeutic Targets ◽  
Class Ii ◽  
Class I

scholarly journals Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

2018 ◽  
Vol 49 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Patrick Lugenbiel ◽  
Katharina Govorov ◽  
Ann-Kathrin Rahm ◽  
Teresa Wieder ◽  
Dominik Gramlich ◽  
...  
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Action Potential Duration ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Class I ◽  
K Channel ◽  
Hdac Inhibition ◽  
Atrial Cardiomyocytes ◽  
Channel Expression

Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

Sign in / Sign up

Export Citation Format

Share Document