Long noncodng RNA lncPostn links TGF-b and p53 signaling pathwas to regulate cardiac fibrosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE184342 | GEO | 2023/09/01
REPOSITORIES: GEO
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Project description:Long noncodng RNA lncPostn links TGF-b and p53 signaling pathwas to regulate cardiac fibrosis
| PRJNA764186 | ENA
Project description:Activated cardiac fibroblasts (CF) play a central role in cardiac fibrosis, a condition associated with most cardiovascular diseases. Conversion of quiescent into activated CF sustains heart integrity upon injury. However, permanence of CF in active state inflicts deleterious heart function effects. Mechanisms underlying this cell state conversion are still not fully disclosed, contributing to a limited target space and lack of effective anti-fibrotic therapies. To prioritize targets for drug development, we studied CF remodeling upon activation at transcriptomic and proteomic levels, using three different cell sources: primary adult CF (aHCF), primary fetal CF (fHCF), and induced pluripotent stem cells derived CF (hiPSC-CF). All cell sources showed a convergent response upon activation, with clear morphological and molecular remodeling associated with cell-cell and cell-matrix interactions. Quantitative proteomic analysis identified known cardiac fibrosis markers, such as FN1, CCN2 and Serpine1, but also revealed targets not previously associated with this condition, including MRC2, IGFBP7 and NT5DC2. Exploring such targets to modulate CF phenotype represents a valuable opportunity for development of anti-fibrotic therapies. Also, we demonstrate that hiPSC-CF is a suitable cell source for preclinical research, displaying significantly lower basal activation level relative to primary cells, while being able to elicit a convergent response upon stimuli.
2023-03-10 | PXD034244 | Pride
Project description:Aims: While Huntingtonâs disease is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. Methods and Results: The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD hearts start at 3mo of age and continue throughout life. The aged BACHD mice develop cardiac fibrosis. The BACHD mice exhibited adaptive physiological changes to chronic isoproterenol challenge; however, the treatment exacerbated fibrotic lesions in the heart. Gene expression analysis indicates a strong tilt toward apoptosis in the young mutant tissue as well as changes in genes involved in cellular metabolism and proliferation. With age, the number of genes with altered expression increased with the largest changes occurring in the cardiovascular disease and cellular metabolism clusters. Conclusions: The BACHD model of HD exhibit a number of changes in cardiovascular function that start early in the disease progress and may provide an explanation for the higher CV risk in HD. These changes are consistent with dysfunction in ANS regulation although the hearts did respond adaptively to β-adrenergic challenge. Gene expression pattern changes are subtle but suggests biomarkers focusing on apoptosis, metabolism, immune function are worth further exploration. Microarray-based gene expression analysis in tissue from transgenic mice and controls at different ages
2016-03-01 | E-GEOD-76593 | biostudies-arrayexpress
Project description:Background. Ageing is one of the main risk factors of cardiovascular disease. Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. In the heart, the consequences of ageing on cardiac pericytes are unknown. Methods. In this study, we have combined single nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 loss of function and finally have perfomed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 loss of function in pericytes on the neighbouring fibroblasts. Results. We showed that ageing reduces the pericyte area and coverage. Single nucleus RNA sequencing analysis further revealed that the expression of the Regulator of G protein signalling 5 (Rgs5) is reduced in old cardiac pericytes. In vivo and in vitro studies showed that the deletion of RGS5 induces morphological changes and a pro-fibrotic gene expression signature characterized by the expression of different extracellular matrix components and growth factors like TGFB2 and PDGFB in pericytes. Indeed, the culture of fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation characterized by the increased expression of α smooth muscle actin in a TFGβ2 dependent mechanism. Conclusions. Our results identify RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.
2024-03-06 | E-MTAB-13841 | biostudies-arrayexpress
Project description:Pericardial fluid (PF) helps maintain homeostatic conditions that facilitate optimal heart function. We have yet to understand how cardiovascular pathologies affect the profile of PF. We hypothesized that human PF contains immune markers that can be affected by different pathologies and contribute to inflammatory-mediated processes, such as fibrosis. PF was collected from patients undergoing cardiac surgery. Multiplex analysis was performed to determine the composition of inflammatory markers and soluble mediators. A gel contraction assay was used to investigate the fibrotic potential of PF. RNA-sequencing was used to elucidate the mechanisms driving the pro-fibrotic properties of PF. With the results of these multiple approaches we show that the acellular component of PF has pro-fibrotic characteristics and suggest putative mechanisms that can explain such observations.
2024-12-06 | GSE262161 | GEO
Project description:Activated cardiac fibroblasts (CF) play a central role in cardiac fibrosis, a condition associated with most cardiovascular diseases. Conversion of quiescent into activated CF sustains heart integrity upon injury. However, permanence of CF in active state inflicts deleterious heart function effects. Mechanisms underlying this cell state conversion are still not fully disclosed, contributing to a limited target space and lack of effective anti-fibrotic therapies. To prioritize targets for drug development, we studied CF remodeling upon activation at transcriptomic and proteomic levels, using three different cell sources: primary adult CF (aHCF), primary fetal CF (fHCF), and induced pluripotent stem cells derived CF (hiPSC-CF). All cell sources showed a convergent response upon activation, with clear morphological and molecular remodeling associated with cell-cell and cell-matrix interactions. Quantitative proteomic analysis identified known cardiac fibrosis markers, such as FN1, CCN2 and Serpine1, but also revealed targets not previously associated with this condition, including MRC2, IGFBP7 and NT5DC2. Exploring such targets to modulate CF phenotype represents a valuable opportunity for development of anti-fibrotic therapies. Also, we demonstrate that hiPSC-CF is a suitable cell source for preclinical research, displaying significantly lower basal activation level relative to primary cells, while being able to elicit a convergent response upon stimuli.
2022-12-01 | GSE202714 | GEO
Project description:Background. Ageing is one of the main risk factors of cardiovascular disease. Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. In the heart, the consequences of ageing on cardiac pericytes are unknown. Methods. In this study, we have combined single nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 loss of function and finally have perfomed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 loss of function in pericytes on the neighbouring fibroblasts. Results. We showed that ageing reduces the pericyte area and coverage. Single nucleus RNA sequencing analysis further revealed that the expression of the Regulator of G protein signalling 5 (Rgs5) is reduced in old cardiac pericytes. In vivo and in vitro studies showed that the deletion of RGS5 induces morphological changes and a pro-fibrotic gene expression signature characterized by the expression of different extracellular matrix components and growth factors like TGFB2 and PDGFB in pericytes. Indeed, the culture of fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation characterized by the increased expression of α smooth muscle actin in a TFGβ2 dependent mechanism. Conclusions. Our results identify RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.
2024-03-13 | E-MTAB-13833 | biostudies-arrayexpress
Project description:Aims: While Huntington’s disease is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. Methods and Results: The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD hearts start at 3mo of age and continue throughout life. The aged BACHD mice develop cardiac fibrosis. The BACHD mice exhibited adaptive physiological changes to chronic isoproterenol challenge; however, the treatment exacerbated fibrotic lesions in the heart. Gene expression analysis indicates a strong tilt toward apoptosis in the young mutant tissue as well as changes in genes involved in cellular metabolism and proliferation. With age, the number of genes with altered expression increased with the largest changes occurring in the cardiovascular disease and cellular metabolism clusters. Conclusions: The BACHD model of HD exhibit a number of changes in cardiovascular function that start early in the disease progress and may provide an explanation for the higher CV risk in HD. These changes are consistent with dysfunction in ANS regulation although the hearts did respond adaptively to β-adrenergic challenge. Gene expression pattern changes are subtle but suggests biomarkers focusing on apoptosis, metabolism, immune function are worth further exploration.
2016-03-01 | GSE76593 | GEO
Project description: Not available
| S-EPMC6635793 | biostudies-literature
Project description:Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in rheumatic disease systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Fos-related antigen-2 (Fosl-2) has been implicated in development of organ fibrosis. Mice overexpressing Fosl-2 (Fosl-2tg) showed interstitial cardiac fibrosis, disorganized connexin43/40 in intercalated discs and deregulated expression of genes controlling conduction system. Fosl-2tg mice developed higher heart rate (HR), prolonged QT intervals, arrhythmias with prevalence of premature ventricular contractions, ventricular tachycardias, II-degree atrio-ventricular blocks and reduced HR variability. Following stimulation with isoproterenol Fosl-2tg mice showed impaired HR response. To assess the role of inflammation in cardiac fibrosis we used Rag2-/-Fosl-2tg mice lacking T/B cells. These mice showed no myocardial fibrosis and ECG abnormalities. Transcriptomics analysis of cardiac Rag-2-/-Fosl-2wt/Rag2-/-Fosl-2tg/Fosl-2tg fibroblasts revealed that systemic inflammation triggered fibrotic and arrhythmogenic alterations while Fosl-2-overexpression mediated profibrotic signature. In human cardiac fibroblasts FOSL-2-overexpression enhanced myofibroblast signature under proinflammatory or profibrotic stimuli. These results demonstrate that under immunofibrotic conditions activator protein 1 transcription factor component Fosl-2 exaggerates myocardial fibrosis, arrhythmias and aberrant response to stress.
2022-10-27 | E-MTAB-12271 | biostudies-arrayexpress