Abstract 375: Insights Into Molecular Mechanism of Cardiovascular Disorder in HIV+ Patients

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Manish Gupta ◽  
Kaylyn Scanlon ◽  
Avni Mukker ◽  
Deepti Gupta ◽  
Jay Rappaport ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Drug Treatment ◽  
Regulation Of Gene Expression ◽  
Cardiovascular Disorder ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Pcr Array ◽  
Hiv Patients ◽  
Antiretroviral Drug

Background: Antiretroviral therapy (ART) improves the survival of people living with HIV (PLHIV); however, the rate of cardiovascular disorder and heart failure is significantly increased among the PLHIV. Molecular basis of heart failure in the PLHIV undergoing antiretroviral drug treatment is not clear. The aim of this study is to explore the role of antiretroviral drugs in post translational modification of histones and its epigenetic regulation of gene expression in cardiomyocytes. Methods and Results: Primary rat ventricular cardiomyocytes were treated with a combination of antiretroviral drugs (5 μM of Atazanavir, Abacavir, Ritonavir and Lamivudine) for 4, 12 and 24 hours, and expression of major histone marks playing a role in gene activation (H3K9ac and H3K27ac) and repression (H3K27me3, H3K9me3) were evaluated by western blotting. Our data suggest that treatment with antiretroviral drugs leads to de-acetylation at H3K9ac and H3K27ac, and promotes methylation at H3K27me3 and H3k9me3. Additionally, the expression of epigenetic modifying enzymes was examined by PCR array in cardiomyocytes treated with antiretroviral drugs. PCR array data show that histone deacetylase enzyme Sirt1/2, and methyltransferase enzyme Suv39h1 and Ezh12 were upregulated in drug treated cardiomyocytes. Further, western blot data show that Sirt1, Suv39h1 and Ezh2 protein expression was significantly upregulated in drugs treated cardiomyocytes. Moreover, expression analysis of human cardiac tissue further shows that expression of Sirt1, Suv39h1 and Ezh2 was significantly upregulated in HIV+ patients heart compares to healthy donor. Mechanistically, our data show that expression of epigenetic modifying enzymes was differentially regulated in drug treated cardiomyocytes which may lead to epigenetic modifications of histone proteins. Conclusion: Antiretroviral drug treatment promotes epigenetic alteration in the chromatin which may lead to a change in gene expression of cardiomyocytes. This study may lead to novel therapeutic strategies for the treatment of heart failure in PLWHA.

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.

scholarly journals Antiretroviral Drugs Regulate Epigenetic Modification of Cardiac Cells Through Modulation of H3K9 and H3K27 Acetylation

2021 ◽  
Vol 8 ◽  
Author(s):  
Shiridhar Kashyap ◽  
Avni Mukker ◽  
Deepti Gupta ◽  
Prasun K. Datta ◽  
Jay Rappaport ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epigenetic Modification ◽  
Critical Role ◽  
Heart Tissue ◽  
Antiretroviral Drugs ◽  
Cardiac Cells ◽  
Histone Deacetylation ◽  
People Living With Hiv ◽  
Pcr Array ◽  
Cellular Hypertrophy

Antiretroviral therapy (ART) has significantly reduced the rate of mortality in HIV infected population, but people living with HIV (PLWH) show higher rates of cardiovascular disease (CVD). However, the effect of antiretroviral (ARV) drug treatment on cardiac cells is not clear. In this study, we explored the effect of ARV drugs in cardiomyocyte epigenetic remodeling. Primary cardiomyocytes were treated with a combination of four ARV drugs (ritonavir, abacavir, atazanavir, and lamivudine), and epigenetic changes were examined. Our data suggest that ARV drugs treatment significantly reduces acetylation at H3K9 and H3K27 and promotes methylation at H3K9 and H3K27, which are histone marks for gene expression activation and gene repression, respectively. Besides, ARV drugs treatment causes pathological changes in the cell through increased production of reactive oxygen species (ROS) and cellular hypertrophy. Further, the expression of chromatin remodeling enzymes was monitored in cardiomyocytes treated with ARV drugs using PCR array. The PCR array data indicated that the expression of epigenetic enzymes was differentially regulated in the ARV drugs treated cardiomyocytes. Consistent with the PCR array result, SIRT1, SUV39H1, and EZH2 protein expression was significantly upregulated in ARV drugs treated cardiomyocytes. Furthermore, gene expression analysis of the heart tissue from HIV+ patients showed that the expression of SIRT1, SUV39H1, and EZH2 was up-regulated in patients with a history of ART. Additionally, we found that expression of SIRT1 can protect cardiomyocytes in presence of ARV drugs through reduction of cellular ROS and cellular hypertrophy. Our results reveal that ARV drugs modulate the epigenetic histone markers involved in gene expression, and play a critical role in histone deacetylation at H3K9 and H3K27 during cellular stress. This study may lead to development of novel therapeutic strategies for the treatment of CVD in PLWH.

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 Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

Nutrients ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 1120 ◽  
Author(s):  
Levi Evans ◽  
Bradley Ferguson
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Drug Efficacy ◽  
Histone Deacetylation ◽  
Epigenetic Modifiers

Approximately 5.7 million U.S. adults have been diagnosed with heart failure (HF). More concerning is that one in nine U.S. deaths included HF as a contributing cause. Current HF drugs (e.g., β-blockers, ACEi) target intracellular signaling cascades downstream of cell surface receptors to prevent cardiac pump dysfunction. However, these drugs fail to target other redundant intracellular signaling pathways and, therefore, limit drug efficacy. As such, it has been postulated that compounds designed to target shared downstream mediators of these signaling pathways would be more efficacious for the treatment of HF. Histone deacetylation has been linked as a key pathogenetic element for the development of HF. Lysine residues undergo diverse and reversible post-translational modifications that include acetylation and have historically been studied as epigenetic modifiers of histone tails within chromatin that provide an important mechanism for regulating gene expression. Of recent, bioactive compounds within our diet have been linked to the regulation of gene expression, in part, through regulation of the epi-genome. It has been reported that food bioactives regulate histone acetylation via direct regulation of writer (histone acetyl transferases, HATs) and eraser (histone deacetylases, HDACs) proteins. Therefore, bioactive food compounds offer unique therapeutic strategies as epigenetic modifiers of heart failure. This review will highlight food bio-actives as modifiers of histone deacetylase activity in the heart.

Regulation of Gene Expression in the Failing Myocardium: Evidence for a Heart Failure Gene Program

1994 ◽  
pp. 7-16
Author(s):  
Arthur M. Feldman ◽  
Vinnette T. Edwards ◽  
Jennifer E. Lawrence ◽  
Randall E. Williams ◽  
Warren D. Rosenblum
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Regulation Of Gene Expression

Abstract 12596: Manipulation of Gut Microbiota Influences Myocardial Mass in Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Takehiro Kamo
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Body Weight ◽  
Gut Microbiota ◽  
Expression Profiles ◽  
Oral Treatment ◽  
Regulation Of Gene Expression ◽  
Heart Weight ◽  
Myocardial Mass ◽  
Antibiotic Cocktail

Introduction: Gut microbiota have developed a close relationship with human host during the co-evolutionary process for millions of years, and they play an essential role in the maintenance of host homeostasis. There is accumulating evidence that an imbalance in the gut microbial communities, referred to as dysbiosis, is associated with human pathologies including cardiovascular diseases. We and others have recently demonstrated that heart failure is associated with gut microbiota dysbiosis using 16S ribosomal RNA gene sequencing of fecal samples from patients with heart failure. This finding suggests a potential significance of gut microbiota in the pathophysiology of heart failure. However, the link between the gut microbiota and the heart remains largely unclear. Hypothesis: We hypothesized that manipulation of gut microbiota influences the structure of the heart. Methods: To determine the effects of gut microbiota depletion, cardiac structure and gene expression were evaluated in mice following treatment with orally administered broad-spectrum antibiotic cocktail. We subsequently explored the effects of administration of a single antibiotic agent on myocardial structure. Results: Antibiotic cocktail-treated mice showed a remarkable decrease in myocardial mass and cardiomyocyte size as compared with untreated mice (mean [±SD] ratio of heart weight to body weight, 3.87±0.25 mg/g in 44 antibiotic-treated mice vs. 4.38±0.21 mg/g in 45 untreated mice). The decrease in myocardial mass was associated with substantial changes in gene expression profiles in the heart, including the expression of genes encoding sarcomere proteins and extracellular matrix proteins. In addition, oral treatment with ampicillin alone led to a significant decrease in myocardial mass (mean [±SD] ratio of heart weight to body weight, 3.52±0.24 mg/g in 11 ampicillin-treated mice vs. 4.10±0.24 mg/g in 12 untreated mice). Conclusions: These results suggest that gut microbiota may modulate myocardial mass through the remote regulation of gene expression in the heart. Our study indicates an intimate relationship between the gut microbiota and the heart, and suggests the potential efficacy of manipulating gut microbiota in the prevention and treatment of heart failure.

scholarly journals In-vitro effects of protease inhibitors on BAX, BCL- 2 and apoptosis in two human breast cell lines

2015 ◽  
Vol Volume 111 (Number 11/12) ◽  
Author(s):  
Gbenga A. Adefolaju ◽  
Kathrine E. Theron ◽  
Margot J. Hosie ◽  
◽  
◽  
...  
Keyword(s):  
Gene Expression ◽  
Protease Inhibitors ◽  
Cell Lines ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Human Breast ◽  
Acridine Orange Staining ◽  
Breast Cell Lines ◽  
Human Breast Cell ◽  
Hiv Aids

Abstract Currently, the treatment of choice of HIV/AIDS in South Africa is the multidrug combination regimen known as HAART (highly active antiretroviral treatment). HAART, which commonly consists of nucleoside or non-nucleoside reverse transcriptase inhibitors and protease inhibitors, has radically decreased mortality and morbidity rates among people living with HIV/AIDS. The emphasis of the original development of the antiretroviral drugs was on clinical effectiveness (reducing mortality). Presently, emphasis has shifted from the initial short- term considerations to the long-term undesirable or harmful effects induced by this treatment regimen. Whether antiretroviral compounds are oncogenic is widely speculated, which led to this investigation into the effects of protease inhibitors on the expression of key apoptotic regulatory genes, BAX and BCL-2, in two human breast cell lines, MCF-7 and MCF-10A by real-time qPCR gene expression and immunofluorescence. The anti-apoptotic effects of the protease inhibitors – LPV/r were also investigated by cell death detection ELISA and acridine orange staining. This study also evaluated the cytotoxicity of the antiretroviral drugs in normal and cancer cell lines of the breast (at clinically relevant concentrations of the drugs and at different time points, 24–96 h), employing the neutral red uptake assay. The drugs and combinations tested did not alter BAX and BCL-2 gene expression and protein expression and localisation in both cell lines. In addition, the protease inhibitors–LPV/r did not inhibit camptothecin-induced apoptosis in both cell lines. We have shown that the protease inhibitors demonstrated varying degrees of cytotoxicity in the breast cells. The resulting DNA damage associated with cytotoxicity is strongly implicated in the processes of tumour initiation.

scholarly journals Dysregulated micro-RNAs and long noncoding RNAs in cardiac development and pediatric heart failure

2020 ◽  
Vol 318 (5) ◽  
pp. H1308-H1315 ◽  
Author(s):  
Lee Toni ◽  
Frehiwet Hailu ◽  
Carmen C. Sucharov
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiovascular Diseases ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Regulation Of Gene Expression ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Cardiovascular Development ◽  
Micro Rnas

Noncoding RNAs (ncRNAs) are broadly described as RNA molecules that are not translated into protein. The investigation of dysregulated ncRNAs in human diseases such as cancer, neurological, and cardiovascular diseases has been under way for well over a decade. Micro-RNAs and long noncoding RNAs (lncRNAs) are the best characterized ncRNAs. These ncRNAs can have profound effects on the regulation of gene expression during cardiac development and disease. Importantly, ncRNAs are significant regulators of gene expression in several congenital heart diseases and can positively or negatively impact cardiovascular development. In this review, we focus on literature involving micro-RNAs and lncRNAs in the context of pediatric cardiovascular diseases, preclinical models of heart failure, and cardiac development.

scholarly journals Antiretroviral Drug Treatment of Individuals that Used Preexposure Prophylaxis (PrEP) Before Diagnosis

2021 ◽  
Author(s):  
David A. M. C. van de Vijver ◽  
Shreoshee Mukherjee ◽  
Jeroen J.A. van Kampen
Keyword(s):  
Drug Resistance ◽  
Drug Treatment ◽  
Treatment Options ◽  
Antiretroviral Drugs ◽  
Anecdotal Evidence ◽  
First Line ◽  
Acute Hiv Infection ◽  
Genotypic Resistance ◽  
Preexposure Prophylaxis ◽  
Antiretroviral Drug

Abstract Purpose of review The antiretroviral drugs, tenofovir and emtricitabine used as preexposure prophylaxis (PrEP), are also used in treatment of HIV. Drug resistance due to PrEP can therefore jeopardize future treatment options. This review discusses treatment of individuals that used PrEP in whom viral mutations against tenofovir (K65R) or emtricitabine (M184I/V) are found. Recent findings Although no studies systematically investigated the optimal treatment of individuals who used PrEP before diagnosis, there is anecdotal evidence that HIV including the K65R and/or M184I/V can be successfully treated using recommended first-line regimens. Summary Drug resistance can be ascribed to use of PrEP while having an unrecognized acute HIV infection, partial adherence to PrEP, and transmission of HIV resistant to PrEP drugs. First-line antiretroviral drug treatment in individuals who used PrEP before diagnosis must be optimized based on genotypic resistance test results. Individuals in whom M184I/V and/or K65R is detected can be treated with dolutegravir-based, bictegravir-based, or darunavir-based regimens plus tenofovir plus lamivudine or emtricitabine. Dual therapy using dolutegravir plus lamivudine is not recommended for induction therapy in individuals with viral mutations against the drugs used as PrEP. There is an urgent need to confirm the anecdotal evidence for successful treatment using first-line regimens.

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