Defining cardiac functional recovery in end-stage heart failure at single cell resolution
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PROVIDER: PRJNA939636 | ENA |
REPOSITORIES: ENA
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Project description:Recovery of cardiac function is the ultimate goal of heart failure therapy yet is infrequently observed and remains poorly understood. Here we characterize the cellular landscape and predictors of cardiac recovery by performing single nucleus RNA-sequencing (snRNA-seq) from 40 heart failure patients who recovered LV systolic function following left ventricular assist device (LVAD) implantation and patients who did not recover and non-diseased donors. We identify cell type specific transcriptional signatures of recovery in all cell types, most prominently in macrophages and fibroblasts. Pro-inflammatory macrophages and inflammatory signalling in fibroblasts were negative predictors of recovery, while downregulation of RUNX1 transcriptional activity in macrophages and fibroblasts was associated with recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of recovery. In a mouse model of cardiac recovery mediated by BRD4 inhibition, we observed a decrease in macrophage and fibroblast Runx1 expression, diminished chromatin accessibility within a Runx1 intronic peak, and acquisition of human recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery.
2023-02-28 | GSE226314 | GEO
Project description:Recovery of cardiac function is the holy grail of heart failure therapy yet is infrequently observed and remains poorly understood. In this study, we performed single-nucleus RNA sequencing from patients with heart failure who recovered left ventricular systolic function after left ventricular assist device implantation, patients who did not recover and non-diseased donors. We identified cell-specific transcriptional signatures of recovery, most prominently in macrophages and fibroblasts. Within these cell types, inflammatory signatures were negative predictors of recovery, and downregulation of RUNX1 was associated with recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of recovery. Cardiac recovery mediated by BET inhibition in mice led to decreased macrophage and fibroblast Runx1 expression and diminished chromatin accessibility within a Runx1 intronic peak and acquisition of human recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery.
| S-EPMC10426763 | biostudies-literature
Project description:Renal failure is characterized by important biological changes resulting in profound pleomorphic physiological effects termed “uremia”, whose molecular causation is not well understood. The data was used to study gene expression changes in uremia using whole genome microarray analysis of peripheral blood from subjects with end-stage renal failure (n=63) and healthy controls (n=20) to obtain insight into the molecular and biological causation of this syndrome. The study was conducted at the University of British Columbia and approved by the human ethics research board. A 3:1 case-control design was employed to compare gene expression in patients with chronic renal failure and healthy controls. Patients with stage 5 renal disease aged 18 to 75 years, who were clinically stable awaiting renal transplantation, were not receiving immunosuppressive medications, and who provided written informed consent were enrolled into the study. Patients were treated according to Canadian Guidelines for Chronic Kidney Disease (13). Normal controls of comparable age and gender to the patients who were screened to ensure freedom from known illness and medical therapy served as comparators.
2012-04-11 | E-GEOD-37171 | biostudies-arrayexpress
Project description:DNA Methylation Reprograms Metabolic Gene Expression in End-Stage Human Heart Failure
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Project description:Role of Endothelial and Mesenchymal cell transitions in heart failure and recovery thereafter
2021-07-01 | GSE161309 | GEO
Project description:Exploring the mechanisms of valvular heart disease (VHD) at the cellular level may be useful to identify new therapeutic targets; however, the comprehensive cellular landscape of non-diseased human cardiac valve leaflets remains unclear. The cellular landscapes of non-diseased human cardiac valve leaflets (five aortic valves, five pulmonary valves, five tricuspid valves, and three mitral valves) from end-stage heart failure patients undergoing heart transplantation were explored using single-cell RNA sequencing (scRNA-seq)
2022-09-13 | GSE213128 | GEO
Project description:This experiment was designed to study the alteration in expression of mRNA is kidney following recovery from transient acute renal failure. The model used was a 52 min. bilateral renal artery clamping, followed by reperfusion, which resulted in a transient loss of renal function, followed by a functional recovery. All tissue in this study was harvested 35 days post-surgery, when renal function was restored, and renal structure largelyy normal. For controls, sham-operated animals were used. An N of 6 post-ischemia reperfusion animals were used with 6 sham-operated controls. For hybridization studies, RNA from one of six post-ischemic acute renal failure animals were compared with with RNA from kidney of six sham-operated control animals. Each ARF vs. sham-operated comparison was performed twice, alternating the cy3 and cy5 label between the two hybridizations for each pair. A second set of hybridizations was carried out using sham vs. sham hybridizations. This was done to get a quantitative analysis of the variation of the biological and microarry platform.
2010-06-10 | E-GEOD-1714 | biostudies-arrayexpress
Project description:This experiment was designed to study the alteration in expression of mRNA is kidney following recovery from transient acute renal failure. The model used was a 52 min. bilateral renal artery clamping, followed by reperfusion, which resulted in a transient loss of renal function, followed by a functional recovery. All tissue in this study was harvested 35 days post-surgery, when renal function was restored, and renal structure largelyy normal. For controls, sham-operated animals were used. An N of 6 post-ischemia reperfusion animals were used with 6 sham-operated controls. For hybridization studies, RNA from one of six post-ischemic acute renal failure animals were compared with with RNA from kidney of six sham-operated control animals. Each ARF vs. sham-operated comparison was performed twice, alternating the cy3 and cy5 label between the two hybridizations for each pair. A second set of hybridizations was carried out using sham vs. sham hybridizations. This was done to get a quantitative analysis of the variation of the biological and microarry platform. Keywords: parallel sample
2005-01-26 | GSE1714 | GEO
Project description:Altered myocardial gene expression from heart failure (HF) has mostly been identified by single-point analysis of end-stage disease. This may miss earlier changes in gene expression that are transient and/or directionally opposite to those observed later. By sampling left ventricular myocardial tissue at different time points in a mouse model of cardiomyopathy, we examined differentially expressed transcripts between non-failing controls, early-HF (2 and 3 days after cardiac insult), peak-HF (10 days) and after recovery from HF (28 days). As a results, we found that gene expression followed varying patterns: Downregulation of metabolic pathways occurred early and was sustained into late stage-HF. In contrast, most signaling pathways undergo a complex biphasic pattern: Calcium signaling, p53, apoptosis and MAP-kinase pathways displayed a bi-directional response, declining early but rising late, while NF-κB-related transcription displayed the opposite pattern. The HF-induced transcriptomic changes were reversed after recovery at 28 days. We conclude that the myocardial transcriptome in evolving HF displays distinct and dynamic transcript clusters. Therapies targeting different phases of HF should consider these dynamic features when identifying high-value targets. Mice expressing mutated estrogen receptor-coupled Cre under transcriptional control of cardiac-specific myosin heavy chain (MerCreMer, MCM, 005650;Jackson Laboratories, Bar Harbor, ME) were back-crossed for >10 generations with C57Bl6/J. Transient cardiomyopathy develops in these mice following 5 day exposure to tamoxifen free base (T5648, Sigma), with peak dysfunction at day 10 and full recovery after 4 weeks. Full transcriptome analyses were generated from flash-frozen left ventricular myocardium at different time points (control = baseline, day 2, day 3, day 10, and day 28).
2014-11-03 | E-GEOD-54681 | biostudies-arrayexpress
Project description:Heart Failure (HF) is a complex clinical disease and leading cause of hospitalization in the United States. Although precision-based treatment options are ultimately preferred, understanding the common underlying features of HF is also needed to develop universal therapies that address its pathogenesis. Among the etiology-independent molecular changes known to occur in HF is a global shift in the heart’s metabolic substrate preference. Transcriptional reprogramming of the heart has been shown to mediate this metabolic switch towards glycolytic metabolism; however, the molecular machinery that reactivate dormant genes remain largely unknown. In the current study, we hypothesized that the cardiac epigenome regulates metabolism via alterations in DNA methylation.
2019-07-25 | GSE123976 | GEO