The antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir, affect inflammation and insulin sensitivity in human coronary endothelial cells through different pathways
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA564860 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir, affect inflammation and insulin sensitivity in human coronary endothelial cells through different pathways.
2020-02-05 | GSE137247 | GEO
Project description:Transcriptome profiling of cardiomyocytes treated with antiretroviral drugs
| PRJNA777924 | ENA
Project description:The use of antiretroviral therapy (ART) improved the life expectancy of HIV patients through the suppression of HIV propagation in host. However, recent studies suggest that long-term use of ART induces comorbid conditions and heart failure in surviving HIV patients. The mechanism associated with the antiretroviral drugs (ARVs) induced cardiotoxicity and heart failure is not clear. In this study, we performed an RNA sequencing with ARV drugs-treated neonatal rat ventricular cardiomyocytes to explore drugs-induced cardiotoxicity. RNA-sequencing data analysis identified 1756 differentially expressed genes (padj<0.05) in cardiomyocytes. Out of 1756 genes, 701 genes were upregulated, and 1055 genes were downregulated in drug-treated cardiomyocytes. Functional enrichment analysis of differentially expressed genes was performed using clusterProfiler R and ingenuity pathway analysis. Our study showed that upregulated genes were linked with the biological processes associated with apoptosis, cellular movement or locomotion, cellular stress, and immune response. In contrast, down-regulated genes were involved in cell division and metabolism. Interestingly, we also found that ARV drugs treatment significantly upregulates the expression of a set of genes involved in cardiac enlargement and hypertrophy in the heart. Collectively, ARVs treatment in cardiomyocytes induces cardiotoxicity through differentially regulation of pathological genes expression in cardiomyocytes.
2021-12-29 | GSE188210 | GEO
Project description:OBJECTIVES:Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance. METHODS:We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects. RESULTS:Dolutegravir reduced inflammation by decreasing NF?B activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NF?B activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable. CONCLUSION:USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.
| S-EPMC6977740 | biostudies-literature
Project description:Analysis of the effects of cell shape on human coronary artery endothelial cell transcription. The hypothesis is that defined alterations in endothelial cell shape uniquely affect the endothelial transcriptome. Human coronary artery endothelial cells were plated onto spatially defined micropatterns (Cytoo) forcing them to conform to Disc, Crossbow, H, Y, or L shapes. As a control, human coronary artery endothelial cells were plated on non-restrictive areas of the Cytoo growth plate. RNA was collected after 24 hours growth on the restricted or non-restricted growth patterns and subjected to whole genome microarray analysis.
2013-06-01 | E-GEOD-43349 | biostudies-arrayexpress
Project description:For many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy. However, many antiretroviral drugs are approved for widespread use following clinical testing only in non-pregnant populations and there may be limited information on potential teratogenicity until pregnancy outcomes are evaluated. The integrase strand transfer inhibitor dolutegravir (DTG) is a frontline antiretroviral drug that is effective in viral suppression of HIV but was previously reported to be associated with a slight increase in the risk for neural tube defects in one study, although this has not been replicated in other cohorts. To directly investigate the potential impact of DTG on human cortical neurogenesis, we measured the effects of daily drug exposure on the early stages of corticogenesis in a human iPSC-based forebrain organoid model. We observed deficits in organoid structure and impaired neurogenesis in DTG-treated organoids compared to vehicle-treated control organoids after 20 or 40 days in culture. Our highest dose of DTG (10µM) resulted in significantly smaller organoids with a reduced density of neural rosette structures compared to vehicle-treated controls. Mechanistically, RNA-sequencing and immunohistological analysis suggests dysregulated amino acid transport and activation of the integrated stress response in the DTG-treated organoids, and functionally, a small molecule integrated stress response inhibitor (ISRIB) could partially rescue increased expression of proteins related to cell cycle regulation. Together, these results illustrate the potential for human iPSC-based strategies to reveal biological processes during neurogenesis that may be affected by therapeutic drugs and provide complementary data in relevant human cell types to augment preclinical investigations of drug safety during pregnancy.
2024-09-18 | GSE275931 | GEO
Project description:Analysis of the effects of cell shape on human coronary artery endothelial cell transcription. The hypothesis is that defined alterations in endothelial cell shape uniquely affect the endothelial transcriptome. Human coronary artery endothelial cells were plated onto spatially defined micropatterns (Cytoo) forcing them to conform to Disc, Crossbow, H, Y, or L shapes. As a control, human coronary artery endothelial cells were plated on non-restrictive areas of the Cytoo growth plate.
2013-06-01 | GSE43349 | GEO
Project description:Analysis of the effects of cell shape on human coronary artery endothelial cell transcription. The hypothesis is that defined alterations in endothelial cell shape uniquely affect the endothelial transcriptome. Human coronary artery endothelial cells were plated onto spatially defined micropatterns (Cytoo) forcing them to conform to Disc, Crossbow, H, Y, or L shapes. As a control, human coronary artery endothelial cells were plated on non-restrictive areas of the Cytoo growth plate. Cells were serum starved for 48 hours prior to mRNA collection.
2013-06-01 | GSE44167 | GEO
Project description:Analysis of the effects of cell shape on human coronary artery endothelial cell transcription. The hypothesis is that defined alterations in endothelial cell shape uniquely affect the endothelial transcriptome. Human coronary artery endothelial cells were plated onto spatially defined micropatterns (Cytoo) forcing them to conform to Disc, Crossbow, H, Y, or L shapes. As a control, human coronary artery endothelial cells were plated on non-restrictive areas of the Cytoo growth plate. Cells were serum starved for 48 hours prior to mRNA collection. RNA was collected after 48 hours growth on the restricted or non-restricted growth patterns and subjected to whole genome microarray analysis.
2013-06-01 | E-GEOD-44167 | biostudies-arrayexpress
Project description:We developed a coronary plaque sampling approach that could be applied broadly in live patients with coronary artery disease (CAD) to obtain molecular and cellular insights into human coronary atherosclerosis. Our approach combined RNA retrieval directly from balloons used in percutaneous coronary interventions (PCI) and inexpensive, low-input RNA-Seq using SMART-seq. We generated SMART-Seq libraries from coronary samples from 27 patients. Of the 27 patients, 13 were confirmed to have stable CAD (sCAD) and 14 confirmed to have been performed on lesions causing acute coronary syndrome (ACS). We applied CIBERSORTx to analyze the SMART-seq data from each of the 27 samples. We found fibroblasts and fibromyoctes were enriched, while smooth muscle cells were reduced, in samples from ACS compared with sCAD patients. We identified 371 genes as significantly differential expressed (q<0.05) between sCAD and ACS patients.
2023-07-10 | GSE236610 | GEO