Antihypertensive drug treatment and susceptibility to SARS-CoV-2 infection in human PSC-derived cardiomyocytes and primary endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE164784 | GEO | 2021/08/26
REPOSITORIES: GEO
Similar Datasets
Project description:The pathogenicity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been attributed to its ability to enter through the membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor. Therefore, it has been heavily speculated that angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy may modulate SARS-CoV-2 infection. In this study, exposure of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and human endothelial cells (hECs) to SARS-CoV-2 identified significant differences in protein coding genes involved in immunity, viral response, and cardiomyocyte/endothelial structure. Specifically, transcriptome changes were identified in the tumor necrosis factor (TNF), interferon α/β, and mitogen-activated protein kinase (MAPK) (hPSC-CMs) as well as nuclear factor kappa-B (NF-κB) (hECs) signaling pathways. However, pre-treatment of hPSC-CMs or hECs with two widely prescribed antihypertensive medications, losartan and lisinopril, did not affect the susceptibility of either cell type to SARS-CoV-2 infection. These findings demonstrate the toxic effects of SARS-CoV-2 in hPSC-CMs/hECs and, taken together with newly emerging multicenter trials, suggest that antihypertensive drug treatment alone does not alter SARS-CoV-2 infection.
| S-EPMC8407952 | biostudies-literature
Project description:Antihypertensive drug treatment and susceptibility to SARS-CoV-2 infection in human PSC-derived cardiomyocytes and primary endothelial cells
| PRJNA691950 | ENA
Project description:Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients accompany with high frequencies of cardiac complications, which prominently contributed to the overall SARS-CoV-2-caused mortality. SARS-CoV-2 genome was reported to encode up to 14 genes. Currently, molecular mechanisms underlying SARS-CoV-2 viral gene-induced cardiac manifestations still remain elusive. Here, we overexpressed Orf9c, a SARS-CoV-2 encoded gene, in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). Multiple genome-wide analyses were performed to investigate the global impacts of Orf9c on hPSC-CMs. The mRNA-seq indicated stress-related signaling pathways, including cell death, immune and inflammation responses, activated by Orf9c. High-throughput proteomics and Co-immunoprecipitation mass spectrometry studies revealed the global influence of Orf9c on the proteome of hPSC-CMs and Orf9c-interactive protein network in hPSC-CMs. Orf9c overexpression elevated protein expressions of key factors essential for apoptosis while suppressing protein factors crucial for ATP synthesis. Further experimental validations confirmed that Orf9c overexpression induced prominent cell death, abnormal calcium handling and electrical properties, and significantly reduced cellular ATP level in hPSC-CMs. Finally, administration of two FDA-approved drugs, Ivermectin and Meclizine, were proven by our study to restore ATP level to prominently ameliorate Orf9c-induced cell death and electrical abnormalities of hPSC-CMs. Overall, we comprehensively manifest global responses of host human heart muscle cells to SARS-CoV-2 gene Orf9c, characterized molecular mechanisms underlying Orf9c-induced cardiac abnormalities, and explored potentially therapeutic approaches to ameliorate cardiac dysfunctions in COVID-19 patients.
2022-02-23 | GSE171370 | GEO
Project description:Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR)
| PRJNA215007 | ENA
Project description:Mass spectrometry is the current technique of choice in studying drug metabolism. High-resolution mass spectrometry (HR-MS) in combination with fragment analysis (MS/MS) has the potential to contribute to rapid advances in this field. However, the data emerging from such fragmentation spectra pose challenges to downstream analysis, given their complexity and size. Here we apply a molecular networking approach to seek drugs and their metabolites, in fragmentation spectra from urine derived from a cohort of 26 patients on antihypertensive therapy. In total, 165 separate drug metabolites were found and structurally annotated (17 by spectral matching and 122 by classification based on a clustered fragmentation pattern). The clusters could be traced to 13 drugs including the known antihypertensives verapamil, losartan and amlopidine. The molecular networking approach also generated networks of endogenous metabolites, including carnitine derivatives, and conjugates containing glutamine, glutamate and trigonelline. The approach offers unprecedented capability in the untargeted identification of drugs and their metabolites at the population level and has great potential to contribute to understanding stratified responses to drugs where differences in drug metabolism may determine treatment outcome. Keywords: Antihypertensive drugs, Drug metabolism, Fragmentation, High-resolution mass spectrometry, Metabolomics, Urine.
2016-05-23 | MTBLS307 | MetaboLights
Project description:To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains of (i.e., hypertensive and normotensive) rats. We chose to use six antihypertensive classes: enalapril (angiotensin converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating -blocker) and hydralazine. In the tested rat strains, four of six drugs, including two renin-angiotensin system (RAS) inhibitors, were effective for BP lowering, whereas the remaining two drugs were not. Besides BP lowering, there appeared to be some inter-drug heterogeneity in phenotypic changes, such as suppressed body weight (Bw) gain and Bw-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by RAS blockade, e.g., for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the RAS/ kallikrein-kinin system (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. The heart data comprises of this submission and part of E-MTAB-9244.
2022-04-15 | E-MTAB-10667 | biostudies-arrayexpress
Project description:To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains of (i.e., hypertensive and normotensive) rats. We chose to use six antihypertensive classes: enalapril (angiotensin converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating beta-blocker) and hydralazine. In the tested rat strains, four of six drugs, including two renin-angiotensin system (RAS) inhibitors, were effective for BP lowering, whereas the remaining two drugs were not. Besides BP lowering, there appeared to be some inter-drug heterogeneity in phenotypic changes, such as suppressed body weight (Bw) gain and Bw-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by RAS blockade, e.g., for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the RAS/ kallikrein-kinin system (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. This submission includes the kidney data.
2022-04-15 | E-MTAB-10672 | biostudies-arrayexpress
Project description:To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains of (i.e., hypertensive and normotensive) rats. We chose to use six antihypertensive classes: enalapril (angiotensin converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating beta-blocker) and hydralazine. In the tested rat strains, four of six drugs, including two renin-angiotensin system (RAS) inhibitors, were effective for BP lowering, whereas the remaining two drugs were not. Besides BP lowering, there appeared to be some inter-drug heterogeneity in phenotypic changes, such as suppressed body weight (Bw) gain and Bw-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by RAS blockade, e.g., for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the RAS/ kallikrein-kinin system (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. This submission includes the kidney data.
2022-04-15 | GSE188349 | GEO
Project description:To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains of (i.e., hypertensive and normotensive) rats. We chose to use six antihypertensive classes: enalapril (angiotensin converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating beta-blocker) and hydralazine. In the tested rat strains, four of six drugs, including two renin-angiotensin system (RAS) inhibitors, were effective for BP lowering, whereas the remaining two drugs were not. Besides BP lowering, there appeared to be some inter-drug heterogeneity in phenotypic changes, such as suppressed body weight (Bw) gain and Bw-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by RAS blockade, e.g., for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the RAS/ kallikrein-kinin system (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. The heart data comprises of this submission and part of ArrayExpress E-MTAB-9244.
2022-04-15 | GSE188348 | GEO
Project description:Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively permissive to SARS-CoV-2 infection both in vitro and upon transplantation in vivo, and that SARS-CoV-2 infection triggers a DA neuron inflammatory and cellular senescence response. A high-throughput screen in hPSC-derived DA neurons identified several FDA approved drugs, including riluzole, metformin, and imatinib, that can rescue the cellular senescence phenotype and prevent SARS-CoV-2 infection. RNA-seq analysis of human ventral midbrain tissue from COVID-19 patients, using formalin-fixed paraffin-embedded autopsy samples, confirmed the induction of an inflammatory and cellular senescence signature and identified low levels of SARS-CoV-2 transcripts. Our findings demonstrate that hPSC-derived DA neurons can serve as a disease model to study neuronal susceptibility to SARS-CoV-2 and to identify candidate neuroprotective drugs for COVID-19 patients. The susceptibility of hPSC-derived DA neurons to SARS-CoV-2 and the observed inflammatory and senescence transcriptional responses suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.
2021-10-20 | GSE174745 | GEO