Abstract P460: Role Of Hopx In Antiretroviral Drugs Induced Cardiac Hypertrophy And Epigenetic Modification

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Shiridhar Kashyap ◽  
Olena Kondrachuk ◽  
Manish K Gupta
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Epigenetic Modification ◽  
Trichostatin A ◽  
Antiretroviral Drugs ◽  
Functional Enrichment ◽  
Hiv Patients ◽  
Acetylation Level

Background: Heart failure is the one of the leading causes of death in HIV patients. Application ofantiretroviral therapy (ART) raise the life expectancy of HIV patients, but survival population show higherrisk of cardiovascular disorder. The aim of this study is to understand the underlying molecular mechanismof antiretroviral drugs (ARVs) induced cardiac dysfunction in HIV patients. Method and Results: To determine the mechanism of ARVs induced cardiac dysfunction, we performeda global transcriptomic profiling in primary cardiomyocytes treated with ARVs. Differentially expressedgenes were identified by DESeq2. Functional enrichment analysis of differentially expressed genes wereperformed using clusterProfiler R and ingenuity pathway analysis. Our data show that ARVs treatmentcauses upregulation of several biological function associated with cardiotoxicity and heart failure.Interestingly, we found that ARV drugs treatment significantly upregulates the expression of a set of genesinvolved cardiac enlargement and hypertrophy in the heart. Global gene expression data were validated inthe cardiac tissue isolated from the HIV patients having history of ART treatment. Interestingly, we foundthat the homeodomain-containing only protein homeobox (HOPX) expression was significantly increasedin transcriptional and translational level in cardiomyocytes treated with ARV drugs as well as in heart tissueof ART treated HIV patients. Further, we performed adenovirus mediated gain in and siRNA mediatedknockdown approach to determine the role of HOPX in ARVs mediated cardiac hypertrophy and epigeneticmodifications. Mechanistically, we found that HOPX expression level plays a key role in ARV drugsmediated increased cardiomyocytes cell size and reduced acetylation level of histone 3 at lysine 9 and lysine27. Furthermore, we found that knockdown of HOPX gene expression blunted the hypertrophy effect ofARV drugs in cardiomyocytes. It is known that HOPX reduces cellular acetylation level through interactionwith HDAC2. In our study, we found that histone deacetylase inhibitor Trichostatin A can restore cellularacetylation level in presence of ARVs. Conclusion: ART treatment causes cardiotoxicity through regulation of fatal gene expression incardiomyocytes and in adult heart. Additionally, we found that HOPX expression is critical in ARVsmediated cardiomyocytes remodeling and epigenetic modification.

scholarly journals HOPX Plays a Critical Role in Antiretroviral Drugs Induced Epigenetic Modification and Cardiac Hypertrophy

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3458
Author(s):  
Shiridhar Kashyap ◽  
Maryam Rabbani ◽  
Isabela de Lima ◽  
Olena Kondrachuk ◽  
Raj Patel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Tissue ◽  
Epigenetic Modification ◽  
Trichostatin A ◽  
Critical Role ◽  
Heart Tissue ◽  
Antiretroviral Drugs ◽  
Neonatal Rat ◽  
People Living With Hiv ◽  
Hiv Patients

People living with HIV (PLWH) have to take an antiretroviral therapy (ART) for life and show noncommunicable illnesses such as chronic inflammation, immune activation, and multiorgan dysregulation. Recent studies suggest that long-term use of ART induces comorbid conditions and is one of the leading causes of heart failure in PLWH. However, the molecular mechanism of antiretroviral drugs (ARVs) induced heart failure is unclear. To determine the mechanism of ARVs induced cardiac dysfunction, we performed global transcriptomic profiling of ARVs treated neonatal rat ventricular cardiomyocytes in culture. Differentially expressed genes were identified by RNA-sequencing. Our data show that ARVs treatment causes upregulation of several biological functions associated with cardiotoxicity, hypertrophy, and heart failure. Global gene expression data were validated in cardiac tissue isolated from HIV patients having a history of ART. Interestingly, we found that homeodomain-only protein homeobox (HOPX) expression was significantly increased in cardiomyocytes treated with ARVs and in the heart tissue of HIV patients. Furthermore, we found that HOPX plays a crucial role in ARVs mediated cellular hypertrophy. Mechanistically, we found that HOPX plays a critical role in epigenetic regulation, through deacetylation of histone, while the HDAC inhibitor, Trichostatin A, can restore the acetylation level of histone 3 in the presence of ARVs.

Abstract 314: BRaf Plays a Major Role in Gene Expression in Cardiomyocytes in Mouse Hearts in vivo

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Michelle A Hardyman ◽  
Stephen J Fuller ◽  
Daniel N Meijles ◽  
Kerry A Rostron ◽  
Sam J Leonard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Braf Mutations ◽  
Gene Markers ◽  
Lv Mass ◽  
Cardiac Volumes

Introduction: Raf kinases lie upstream of ERK1/2 with BRaf being the most highly expressed and having the highest basal activity. V600E BRaf mutations constitutively activate ERK1/2 and are common in cancer. The role of BRaf in the adult heart is yet to be established. ERK1/2 regulate cardiomyocyte gene expression, promoting cardiac hypertrophy and cardioprotection, but effects of ERK1/2 may depend on signal strength. Hypothesis: Our hypotheses are that BRaf is critical in regulating ERK1/2 signaling in cardiomyocytes and, whilst moderate ERK1/2 activity is beneficial, excessive ERK1/2 activity is detrimental to the heart. Methods: We generated heterozygote mice for tamoxifen- (Tam-) inducible cardiomyocyte-specific knockin of V600E in the endogenous BRaf gene. Mice (12 wks) received 2 injections of Tam or vehicle on consecutive days (n=4-10 per group). Kinase activities and mRNA expression were assessed by immunoblotting and qPCR. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Results: V600E knockin did not affect overall BRaf or cRaf levels in mouse hearts, but significantly increased ERK1/2 activities within 48 h (1.51±0.05 fold). Concurrently, mRNAs for hypertrophic gene markers including BNP and immediate early genes (IEGs) increased signficantly. At 72 h, expression of BNP, Fosl1, Myc, Ereg and CTGF increased further, other IEGs (Jun, Fos, Egr1, Atf3) declined, and ANF was upregulated. In contrast, expression of α and β myosin heavy chain mRNAs was substantially downregulated (0.46/0.41±0.05 relative to controls). Within 72 h, left ventricular (LV) mass and diastolic LV wall thickness had increased (1.23±0.05 relative to controls), but cardiac function was severely compromised with significant decreases in ejection fraction and cardiac output (0.53/0.68±0.09 relative to controls) associated with increased LV internal diameters and cardiac volumes. Conclusions: Endogenous cardiomyocyte BRaf is sufficient to activate ERK1/2 in mouse hearts and induce cardiac hypertrophy associated with dynamic temporal changes in gene expression. However, excessive activation of ERK1/2 in isolation is detrimental to cardiac function.

Abstract 026: Role of Tank in the Regulation of Pathological Cardiac Hypertrophy

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hongliang Li ◽  
Peng Zhang
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Akt Inhibitor ◽  
Aortic Banding ◽  
Pathological Cardiac Hypertrophy

TRAF associated NF-κB activator (TANK) is adaptor protein which was identified as a negative regulator of TRAF-, TBK1- and IKKi-mediated signal transduction through its interaction with them. Besides its important roles in the regulation of immune response, it has been reported that TANK contributes to the development of autoimmune nephritis and osteoclastogenesis. However, its functions in cardiovascular diseases especially cardiac hypertrophy is largely unknown. In the present study, we interestingly observed that TNAK expression is increased by 240% in human hypertrophic cardiomyopathy(HCM)tissue and 320% in mouse hypertrophic heart after aortic banding (AB), indicating that TANK may be involved in the pathogenesis of this diseases. Subsequently, cardiac-specific TANK knockout (TANK-KO) and transgenic(TANK-TG)mice were generated and subjected to AB for 4 to 8 weeks. Our results demonstrated that TANK deficiency prevented against cardiac hypertrophy and fibrosis induced by pressure overload,as evidenced by that the cardiomyocytes enlargement and fibrosis formation was reduced by about 34% and 43% compared with WT mice, respectively. Conversely, TANK-TG mice showed an aggravated effect on cardiac hypertrophy in response to pressure overload with 36% and 47% increase of cardiomyocytes enlargement and fibrosis formation compared with non-transgenic mice. More importantly, in vitro experiments further revealed that TANK overexpression which was mediated by adenovirus in the cardiomyocytes dramatically increased the cell size and the expression of hypertrophic markers, whereas TANK knockdown had an opposite function. Mechanistically, we discovered that AKT signaling was activated (230%) in the hearts of TANK-TG mice, while being greatly reduced in TNAK-KO hearts after aortic banding. Moreover, blocking AKT/GSK3β signaling with a pharmacological AKT inhibitor reversed cardiac dysfunction of TANK-TG mice. Collectively, our data show that TNAK acts as a novel regulator of pathological cardiac hypertrophy and may be a promising therapeutic targets.

scholarly journals Demethylation alters transcriptome profiling of buds and leaves in ‘Kyoho’ grape

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Haoran Jia ◽  
Zibo Zhang ◽  
Ehsan Sadeghnezhad ◽  
Qianqian Pang ◽  
Shangyun Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Epigenetic Modification ◽  
Deep Understanding ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Glutathione Metabolism ◽  
Endogenous Factors

Abstract Background Grape buds and leaves are directly associated with the physiology and metabolic activities of the plant, which is monitored by epigenetic modifications induced by environment and endogenous factors. Methylation is one of the epigenetic regulators that could be involved in DNA levels and affect gene expression in response to stimuli. Therefore, changes of gene expression profile in leaves and bud through inhibitors of DNA methylation provide a deep understanding of epigenetic effects in regulatory networks. Results In this study, we carried out a transcriptome analysis of ‘Kyoho’ buds and leaves under 5-azacytidine (5-azaC) exposure and screened a large number of differentially expressed genes (DEGs). GO and KEGG annotations showed that they are mainly involved in photosynthesis, flavonoid synthesis, glutathione metabolism, and other metabolic processes. Functional enrichment analysis also provided a holistic perspective on the transcriptome profile when 5-azaC bound to methyltransferase and induced demethylation. Enrichment analysis of transcription factors (TFs) also showed that the MYB, C2H2, and bHLH families are involved in the regulation of responsive genes under epigenetic changes. Furthermore, hormone-related genes have also undergone significant changes, especially gibberellin (GA) and abscisic acid (ABA)-related genes that responded to bud germination. We also used protein-protein interaction network to determine hub proteins in response to demethylation. Conclusions These findings provide new insights into the establishment of molecular regulatory networks according to how methylation as an epigenetic modification alters transcriptome patterns in bud and leaves of grape.

scholarly journals Role of COL3A1 and POSTN on Pathologic Stages of Esophageal Cancer

2020 ◽  
Vol 19 ◽  
pp. 153303382097748
Author(s):  
Shao-wei Zhang ◽  
Nan Zhang ◽  
Na Wang
Keyword(s):  
Gene Expression ◽  
Esophageal Cancer ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Gene Expression Omnibus ◽  
Functional Enrichment ◽  
Protein Protein Interaction ◽  
And Control ◽  
The Impact

Background: Esophageal cancer (EC) is a primary malignant tumor originating from the esophageal of the epithelium. Surgical resection is a potential treatment for EC, but this is only appropriate for patients who have locally resectable lesions suitable for surgery. However, most patients with EC are at a late stage when diagnosed. Therefore, there is an urgent need to further explore the pathogenesis of EC to enable early diagnosis and treatment. Methods: Our study downloaded 2 expression spectrum datasets (GSE92396 and GSE100942) in the Gene Expression Omnibus (GEO) database. GEO2 R was used to identify the Differentially expressed genes (DEGs) between the samples of EC and control. Using the DAVID tool to make the Functional enrichment analysis. Constructing A protein–protein interaction (PPI) network. Identifying the Hub genes. The impact of hub gene expression on overall survival and their expression based on immunohistochemistry were analyzed. Associated microRNAs were also predicted. Results: There were 36 common DEGs identified. The analysis of GO and KEGG results shown that the variations were predominantly concentrated in the extracellular matrix (ECM), ECM organization, DNA binding, platelet activation, and ECM-receptor interactions. COL3A1 and POSTN had high expression in EC tissues which was compared with their expression in healthy tissues. Analysis of pathologic stages showed that when COL3A1 and POSTN were highly expressed, the stage of the pathologic of EC patients was relatively high (P < 0.005). Conclusions: COL3A1 and POSTN may play an important role in the advancement and occurrence of EC. These genes could provide some novel ideas and basis for the diagnosis and targeted treatment of EC.

Azacitidine, as a DNMT Inhibitor Decreases hTERT Gene Expression and Telomerase Activity More Effective Compared with HDAC Inhibitor in Human Head and Neck Squamous Cell Carcinoma Cell Lines

2020 ◽  
Vol 14 (1) ◽  
pp. 60-67
Author(s):  
Sepideh Atri ◽  
Nikoo Nasoohi ◽  
Mahshid Hodjat
Keyword(s):  
Gene Expression ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
Trichostatin A ◽  
Telomerase Activity ◽  
Htert Gene ◽  
Deacetylase Inhibitor

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most fatal malignancies worldwide and despite using various therapeutic strategies for the treatment of HNSCC, the surveillance rate is low. Telomerase has been remarked as the primary targets in cancer therapy. Considering the key regulatory role of epigenetic mechanisms in controlling genome expression, the present study aimed to investigate the effects of two epigenetic modulators, a DNA methylation inhibitor and a histone deacetylase inhibitor on cell migration, proliferation, hTERT gene expression, and telomerase activity in HNSCC cell lines. Methods: Human HNSCC cell lines were treated with Azacitidine and Trichostatin A to investigate their effects on telomerase gene expression and activity. Cell viability, migration, hTERT gene expression, and telomerase activity were studied using MTT colorimetric assay, scratch wound assay, qRT-PCR, and TRAP assay, respectively. Results: Azacitidine at concentrations of ≤1μM and Trichostatin A at 0.1 to 0.3nM concentrations significantly decreased FaDu and Cal-27 cells migration. The results showed that Azacitidine significantly decreased hTERT gene expression and telomerase activity in FaDu and Cal-27 cell lines. However, there were no significant changes in hTERT gene expression at different concentrations of Trichostatin A in both cell lines. Trichostatin A treatment affected telomerase activity at the high dose of 0.3 nM Trichostatin A. Conclusion: The findings revealed that unlike histone deacetylase inhibitor, Azacitidine as an inhibitor of DNA methylation decreases telomerase expression in HNSCC cells. This might suggest the potential role of DNA methyltransferase inhibitors in telomerase-based therapeutic approaches in squamous cell carcinoma.

Abstract 182: Class I Histone Deacetylase Inhibition Represses the Upregulation of Sodium-Calcium Exchanger Expression in Cardiac Hypertrophy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Santhosh K Mani ◽  
Olga Chernysh ◽  
Mona S Li ◽  
Ludivine Renaud ◽  
Michael G Janech ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Hdac Inhibitor ◽  
Trichostatin A ◽  
Class Ii ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Therapeutic Modality ◽  
Specific Class ◽  
Hdac Activity

Background: Histone deacetylases (HDACs) play an important role in the alteration of gene expression during cardiac hypertrophy and failure. Our previous study demonstrated that acetylated Nkx2.5 is associated with the Class I/II HDAC complex, HDAC5/1/2 at the Ncx1 promoter, and deacetylated Nkx2.5 is associated with the transcriptional activator and histone acetylase, p300 in a mutually exclusive manner. Inhibition of HDACs by the Class I/II inhibitor, trichostatin A (TSA) prevents deacetylation of Nkx2.5 and recruitment of p300 to the Ncx1 promoter, thereby repressing its upregulation. Objective: To assess the specific roles of HDAC1, 2 and 5 in the regulation of Ncx1 gene expression and determine the specific Nkx2.5 lysine(s) undergoing acetylation or deacetylation, which mediates Ncx1 upregulation. Results: Treatment of isolated adult cardiomyocytes with the selective class I HDAC inhibitor, BML210, prevented alpha- and beta-adrenergic stimulated upregulation of Ncx1 expression, whereas treatment with the specific class II HDAC inhibitor, dPAHA did not. Interestingly, the HDAC5 knockout prevented NCX1 upregulation after 72 hr trans-aortic constriction (TAC) in mice. In order to determine which Nkx2.5 lysine(s) is deacetylated by HDAC1/2, we performed mass spectrometry analysis. The Nkx2.5 gene contains 15 lysine moieties, and LC-MS/MS analysis demonstrates that Nkx2.5 is acetylated on two conserved lysine residues. Conclusion: Class I HDAC activity is required for Ncx1 expression but not class II HDAC activity (HDAC5). However, the loss of HDAC5 prevents Ncx1 upregulation because it may act as a scaffold to recruit the factors required for Ncx1 promoter activation. These results suggest that HDAC inhibition may represent a novel therapeutic modality for hypertrophy and heart failure.

Role of the Epigenome in Heart Failure

2020 ◽  
Vol 100 (4) ◽  
pp. 1753-1777 ◽  
Author(s):  
Roberto Papait ◽  
Simone Serio ◽  
Gianluigi Condorelli
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Epigenetic Modification ◽  
Heart Function ◽  
Histone Deacetylation ◽  
Cardiac Phenotype ◽  
Different Types ◽  
Response To Stress ◽  
Histone Methylation And Acetylation

Gene expression is needed for the maintenance of heart function under normal conditions and in response to stress. Each cell type of the heart has a specific program controlling transcription. Different types of stress induce modifications of these programs and, if prolonged, can lead to altered cardiac phenotype and, eventually, to heart failure. The transcriptional status of a gene is regulated by the epigenome, a complex network of DNA and histone modifications. Until a few years ago, our understanding of the role of the epigenome in heart disease was limited to that played by histone deacetylation. But over the last decade, the consequences for the maintenance of homeostasis in the heart and for the development of cardiac hypertrophy of a number of other modifications, including DNA methylation and hydroxymethylation, histone methylation and acetylation, and changes in chromatin architecture, have become better understood. Indeed, it is now clear that many levels of regulation contribute to defining the epigenetic landscape required for correct cardiomyocyte function, and that their perturbation is responsible for cardiac hypertrophy and fibrosis. Here, we review these aspects and draw a picture of what epigenetic modification may imply at the therapeutic level for heart failure.

scholarly journals Slowing Down Ageing: The Role of Nutrients and Microbiota in Modulation of the Epigenome

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1251 ◽  
Author(s):  
Agnieszka Gadecka ◽  
Anna Bielak-Zmijewska
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Structural Changes ◽  
Epigenetic Modification ◽  
Condensed Chromatin ◽  
Gene Promoters ◽  
Methylation Of Dna ◽  
Age Related ◽  
Altered Gene

The human population is getting ageing. Both ageing and age-related diseases are correlated with an increased number of senescent cells in the organism. Senescent cells do not divide but are metabolically active and influence their environment by secreting many proteins due to a phenomenon known as senescence associated secretory phenotype (SASP). Senescent cells differ from young cells by several features. They possess more damaged DNA, more impaired mitochondria and an increased level of free radicals that cause the oxidation of macromolecules. However, not only biochemical and structural changes are related to senescence. Senescent cells have an altered chromatin structure, and in consequence, altered gene expression. With age, the level of heterochromatin decreases, and less condensed chromatin is more prone to DNA damage. On the one hand, some gene promoters are easily available for the transcriptional machinery; on the other hand, some genes are more protected (locally increased level of heterochromatin). The structure of chromatin is precisely regulated by the epigenetic modification of DNA and posttranslational modification of histones. The methylation of DNA inhibits transcription, histone methylation mostly leads to a more condensed chromatin structure (with some exceptions) and acetylation plays an opposing role. The modification of both DNA and histones is regulated by factors present in the diet. This means that compounds contained in daily food can alter gene expression and protect cells from senescence, and therefore protect the organism from ageing. An opinion prevailed for some time that compounds from the diet do not act through direct regulation of the processes in the organism but through modification of the physiology of the microbiome. In this review we try to explain the role of some food compounds, which by acting on the epigenetic level might protect the organism from age-related diseases and slow down ageing. We also try to shed some light on the role of microbiome in this process.

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