Abstract 355: Post-translational Modification of Histone Variants in Cardiac Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Mickey Miller ◽  
Aman Makaju ◽  
Li Wang ◽  
Sarah Franklin
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Differential Expression Analysis ◽  
Pressure Overload ◽  
Histone Variants ◽  
Neonatal Rat ◽  
Global Changes ◽  
Label Free ◽  
Post Translational Modification ◽  
Post Translational Modifications

While global changes in gene expression are a hallmark of cardiac hypertrophy, much less is known regarding the epigenetic factors driving these changes. Local chromatin packing and gene accessibility, which governs transcriptional status, has been correlated with specific post-translational modifications on the histone tails of nucleosomes occupying these regions. However, the specific alterations in histone post-translational modifications driving gene expression changes during cardiac hypertrophy are largely unknown. To identify myocyte specific changes in histone post-translational modifications during cardiac hypertrophy we performed label-free quantitation of nuclear proteins from isolated neonatal rat ventricular myocytes exposed to the hypertrophic agonists, phenylephrine and isoproterenol. Peptide samples were analyzed on a Thermo Orbitrap Velos Pro mass spectrometer using CID & HCD fragmentation. Differential expression analysis was performed using the Progenesis LC-MS software where modified histone peptides were normalized against total protein expression. We observed multiple known and novel post-translational modifications on each of the four core histones, many of which changed in the setting of hypertrophy. To validate these findings in an animal model we performed the same analysis of histone post-translational modifications from cardiac tissue of mice under basal conditions or after pressure-overload induced hypertrophy. This study provides the first global characterization of myocyte specific changes in histone post-translational modifications in cardiac hypertrophy and highlight basic mechanisms of genomic reprogramming operative in disease.

Induction of S100β in Myocardium: An Intrinsic Inhibitor of Cardiac Hypertrophy

1998 ◽  
Vol 23 (4) ◽  
pp. 377-389 ◽  
Author(s):  
Thomas G. Parker ◽  
James N. Tsoporis
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Cardiac Hypertrophy ◽  
Calcium Binding ◽  
Cardiac Myocyte ◽  
Human Subjects ◽  
S100 Protein ◽  
Pressure Overload ◽  
Cellular Growth ◽  
Neonatal Rat

Cardiac hypertrophy induced by pressure overload and following myocardial infarction entails regulation of myocardial gene expression, recapitulating an embryonic phenotype, including activation of fetal β-myosin heavy chain and skeletal α-actin. Progressive hypertrophy and alterations in gene expression may contribute to myocardial failure. Although signaling pathways that contribute to hypertrophy development have been identified, intrinsic cardiac regulators that limit hypertrophic response have not been determined. The β subunit of S100 protein is induced in the myocardium of human subjects and an experimental rat model following myocardial infarction. Forced S100β expression in neonatal rat cardiac myocyte cultures and high level expression of S100β in transgenic mice hearts inhibit cardiac hypertrophy and the associated phenotype by modulating protein kinase C-dependent pathways. S100β expression is probably a component of the myocyte response to trophic stimulation that serves as a negative feedback mechanism to limit cellular growth and the associated alterations in gene expression. Key words: gene expression, cardiac myocytes, growth factors, heart failure, calcium-binding proteins

scholarly journals Bakuchiol protects against pathological cardiac hypertrophy by blocking NF-κB signaling pathway

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Zheng Wang ◽  
Lu Gao ◽  
Lili Xiao ◽  
Lingyao Kong ◽  
Huiting Shi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Oral Gavage ◽  
Aortic Banding ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy ◽  
First Time

Bakuchiol (Bak), a monoterpene phenol isolated from the seeds of Psoralea corylifolia, has been widely used to treat a large variety of diseases in both Indian and Chinese folkloric medicine. However, the effects of Bak on cardiac hypertrophy remain unclear. Therefore, the present study was designed to determine whether Bak could alleviate cardiac hypertrophy. Mice were subjected to aortic banding (AB) to induce cardiac hypertrophy model. Bak of 1 ml/100 g body weight was given by oral gavage once a day from 1 to 8 weeks after surgery. Our data demonstrated for the first time that Bak could attenuate pressure overload-induced cardiac hypertrophy and could attenuate fibrosis and the inflammatory response induced by AB. The results further revealed that the effect of Bak on cardiac hypertrophy was mediated by blocking the activation of the NF-κB signaling pathway. In vitro studies performed in neonatal rat cardiomyocytes further proved that the protective effect of Bak on cardiac hypertrophy is largely dependent on the NF-κB pathway. Based on our results, Bak shows profound potential for its application in the treatment of pathological cardiac hypertrophy, and we believe that Bak may be a promising therapeutic candidate to treat cardiac hypertrophy and heart failure.

A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload

2018 ◽  
Vol 115 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Andrea Grund ◽  
Malgorzata Szaroszyk ◽  
Janina K Döppner ◽  
Mona Malek Mohammadi ◽  
Badder Kattih ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Binding Protein ◽  
Treatment Strategies ◽  
Pressure Overload ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

scholarly journals Emodin Attenuates Pathological Cardiac Hypertrophy by Regulating Gene Expression Through Acetyl-histone-mediated Actions (P06-036-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Levi Evans ◽  
Bradley Ferguson
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Histone Acetylation ◽  
Regulation Of Gene Expression ◽  
Epigenetic Modifications ◽  
Neonatal Rat ◽  
Heart Health ◽  
Hdac Activity ◽  
Pathological Cardiac Hypertrophy ◽  
Epigenetic Regulators

Abstract Objectives Epigenetic modifications regulate gene expression without changing DNA sequence and are reversible, highlighting their therapeutic potential for heart failure. Recent evidence suggests that food compounds can reverse these stress-induced epigenetic modifications, yet few studies have characterized their role as epigenetic regulators of heart health. Our objective tested the hypothesis that Emodin, an Antraquinone found in rhubarb, blocked pathological cardiac hypertrophy via acetyl-histone-mediated gene expression changes. Methods To test this hypothesis, neonatal rat ventricular myocytes (NRVMs) were stimulated with phenylephrine (PE, 10 μM) to induce receptor-mediated pathological cardiac hypertrophy in the absence or presence of vehicle control or Emodin (10 μM) for 48 hours. Cells were subsequently 1) fixed for immunostaining and cell size quantification, 2) lysed for protein to assess HDAC activity and histone acetylation or 3) lysed for RNA to analyze transcriptome–wide changes in gene expression. A minimum of three experiments with an n = 3/group was performed and data quantified. One-way ANOVA with Tukey's post-hoc was performed unless otherwise specified. p < 0.05 was considered significant. Results Emodin significantly blocked PE-induced hypertrophy. Emodin significantly inhibited HDAC activity concomitant to increased histone acetylation. Lastly, Emodin reversed stress-induced changes in gene expression. Conclusions Our data suggest that Emodin inhibited pathological cardiac hypertrophy via acetyl-histone dependent regulation of gene expression. While animal studies are currently underway to examine the epigenetic actions for emodin in cardiac protection, our results support the role for food compounds like Emodin as epigenetic regulators of heart health. Funding Sources This work is supported by the USDA NIFA (Hatch-NEV00727), the Dennis Meiss & Janet Ralston Fund for Nutri-epigenetic Research and by the National Institute for General Medical Sciences (NIGMS) of the NIH (P20 GM130459) to B.S.F. Core facilities used for Research were supported by NIGMS of the NIH (P20 GM103554).

scholarly journals Epigenetic Regulation of Myogenesis: Focus on the Histone Variants

2021 ◽  
Vol 22 (23) ◽  
pp. 12727
Author(s):  
Joana Esteves de Lima ◽  
Frédéric Relaix
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Epigenetic Regulation ◽  
Muscle Development ◽  
Regulation Of Gene Expression ◽  
Histone Variants ◽  
Myoblast Differentiation ◽  
Post Translational Modifications ◽  
Differentiation Status

Skeletal muscle development and regeneration rely on the successive activation of specific transcription factors that engage cellular fate, promote commitment, and drive differentiation. Emerging evidence demonstrates that epigenetic regulation of gene expression is crucial for the maintenance of the cell differentiation status upon division and, therefore, to preserve a specific cellular identity. This depends in part on the regulation of chromatin structure and its level of condensation. Chromatin architecture undergoes remodeling through changes in nucleosome composition, such as alterations in histone post-translational modifications or exchange in the type of histone variants. The mechanisms that link histone post-translational modifications and transcriptional regulation have been extensively evaluated in the context of cell fate and differentiation, whereas histone variants have attracted less attention in the field. In this review, we discuss the studies that have provided insights into the role of histone variants in the regulation of myogenic gene expression, myoblast differentiation, and maintenance of muscle cell identity.

scholarly journals Molecular Mechanism of Nuclear Tau Accumulation and its Role in Protein Synthesis

2020 ◽  
Author(s):  
Miguel Portillo ◽  
Ekaterina Eremenko ◽  
Shai Kaluski ◽  
Lior Onn ◽  
Daniel Stein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Protein Synthesis ◽  
Energy Production ◽  
Protein Translation ◽  
Nuclear Accumulation ◽  
Rrna Synthesis ◽  
Global Changes ◽  
Post Translational Modifications ◽  
Dna Damage Signaling

AbstractSeveral neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegenerative patients. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage result in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression affecting protein translation, synthesis and energy production. Tau-K174Q expressing cells showed changes in the nucleolus increasing their intensity and number, as well as in rRNA synthesis leading to an increase in protein translation and ATP reduction. Concomitantly, AD patients showed increased Nucleolin and a decrease in SIRT6 levels. AD patients present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD patients is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation and nucleolar dysfunction.

scholarly journals Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload

2021 ◽  
Vol 12 ◽  
Author(s):  
Nan Zhang ◽  
Hai-Han Liao ◽  
Hong Feng ◽  
Shan-Qi Mou ◽  
Wen-Jing Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Conditional Knockout ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Genetic Toxicity ◽  
And Oxidative Stress ◽  
Dependent Pathway

Objectives: Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2.Methods and results: Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60–70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy in vitro. Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout.Conclusion: This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.

scholarly journals Analyzing gene expression profiles with preliminary validations in cardiac hypertrophy induced by pressure overload

2018 ◽  
Vol 96 (8) ◽  
pp. 701-709 ◽  
Author(s):  
Jing Gao ◽  
Yuhong Li ◽  
Tongmei Wang ◽  
Zhuo Shi ◽  
Yiqi Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Pressure Overload ◽  
Enrichment Analysis ◽  
Receptor Interaction ◽  
Pathway Enrichment Analysis ◽  
Ontology Term ◽  
The Common

The aim of this study was to identify the key genes involved in the cardiac hypertrophy (CH) induced by pressure overload. mRNA microarray data sets GSE5500 and GSE18801 were downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were screened using the Limma package; then, functional and pathway enrichment analysis were performed for common DEGs using the Database for Annotation, Visualization and Integrated Discovery database. Furthermore, the top DEGs were further validated using quantitative PCR in the hypertrophic heart tissue induced by isoprenaline. A total of 113 common DEGs with absolute fold change > 0.5, including 60 significantly upregulated DEGs and 53 downregulated DEGs, were obtained. Gene ontology term enrichment analysis suggested that common upregulated DEG were mainly enriched in neutrophil chemotaxis, extracellular fibril organization, and cell proliferation; and the common downregulated genes were significantly enriched in ion transport, endoplasmic reticulum, and dendritic spine. Kyoto Encyclopedia of Genes and Genomes pathway analysis found that the common DEGs were mainly enriched in extracellular matrix receptor interaction, phagosome, and focal adhesion. Additionally, the expression of Mfap4, Ltbp2, Aspn, Serpina3n, and Cnksr1 were upregulated in the model of CH, while the expression of Anp32a was downregulated. The current study identified the key deregulated genes and pathways involved in the CH, which could shed new light to understand the mechanism of CH.

Inhibition of angiotensin II-induced hypertrophy and cardiac dysfunction by North American ginseng (Panax quinquefolius)

2020 ◽  
Author(s):  
Xilan Tang ◽  
Tracey Gan ◽  
Chian Ju Jong ◽  
Venkatesh Rajapurohitam ◽  
Morris Karmazyn
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
North American ◽  
Glucose Oxidation ◽  
American Ginseng ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Expression Levels

We determined whether North American ginseng mitigates the effect of angiotensin II on hypertrophy and heart failure. Angiotensin II (0.3 mg/kg) was administered to rats for 2 or 4 weeks in the presence or absence of ginseng pretreatment. The effect of ginseng (10 μg/mL) on angiotensin II (100 nM) induced hypertrophy was also determined in neonatal rat ventricular myocytes. We also determined effects of ginseng on fatty acid and glucose oxidation by measuring gene and protein expression levels of key factors. Angiotensin II treatment for 2 and 4 weeks induced cardiac hypertrophy as evidenced by increased heart weights as well as the upregulation of the hypertrophy-related fetal gene expression levels with all effects being abolished by ginseng. Ginseng also reduced abnormalities in left ventricular function as well as the angiotensin-induced increased blood pressure. In myocytes, ginseng abolished the hypertrophic response to angiotensin II as assessed by surface area and gene expression of molecular markers of hypertrophy. Ginseng modulated angiotensin II-induced abnormalities in gene expression and protein levels of CD36, CPT1M, Glut4 and PDK4 in vivo and in vitro. In conclusion, ginseng suppresses angiotensin II induced cardiac hypertrophy and dysfunction which is related to normalization of fatty acid and glucose oxidation.

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