Progerin triggers a phenotypic switch in VSMC that causes replication stress and an aging-associated secretory signature
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ABSTRACT:
PROVIDER: PRJNA817614 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18352942_1.fastq.gz | Fastqsanger.gz | |||
| SRR18352942_2.fastq.gz | Fastqsanger.gz | |||
| SRR18352943_1.fastq.gz | Fastqsanger.gz | |||
| SRR18352943_2.fastq.gz | Fastqsanger.gz | |||
| SRR18352944_1.fastq.gz | Fastqsanger.gz |
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Project description:Hutchinson Gilford Progeria Syndrome is a premature aging disease caused by LMNA gene mutation and the production of a truncated lamin A protein “progerin” that elicits cellular and organismal toxicity. Progerin accumulates in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients' autopsies show that vessel stiffening, and aortic atherosclerosis is accompanied by VSMC depletion in the medial layer, altered extracellular matrix (ECM), and thickening of the adventitial layer. Mechanisms whereby progerin causes massive VSMC loss and vessel alterations remain poorly understood. Mature VSMC retain phenotypic plasticity and can switch to a synthetic/proliferative phenotype. Here we show that progerin expression in human and mouse VSMC causes a switch towards the synthetic/proliferative phenotype. This switch elicits some level of replication stress in normal cells, which is exacerbated in the presence of progerin, leading to telomere fragility, genomic instability, and ultimately VSMC death. Importantly, calcitriol prevents replication stress, telomere fragility, and genomic instability, reducing VSMC death. In addition, RNAseq analysis shows induction of a profibrotic and proinflammatory aging-associated secretory phenotype upon progerin expression in human primary VSMC. Our data suggest that phenotypic switch-induced replication stress might be an underlying cause of VSMC loss in progeria, which together with loss of contractile features and gain of profibrotic and proinflammatory signatures contribute to vascular stiffness in HGPS. Preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might ameliorate CVD in HGPS patients
2022-03-23 | GSE198983 | GEO
Project description:We applied the transcriptome profiling (RNA-seq) for high-throughput profiling of genes changes in VSMC dedifferentiation. Rat primary VSMCs were divided into 3 groups, control, PDGF-BB, PDGF-BB+PJ34,and mRNA sequence were performed. We found that PDGF-BB could upregualted the genes involved in cell proliferation and migration, and downregulated the VSMC contractile genes, all of which could be reversed by PARP inhibitor PJ34. Then we knockdowned the co-factor Myocardin in VSMCs, and found the above effects of PJ34 were nearly abolished.Our study first provided the transcription changes by RNA-seq in VSMC dedifferentiation, and demonstrated the key roles of PARP1 and the PARylation process in VSMC phenotypic switch.
2018-09-20 | GSE103995 | GEO
Project description:Hutchinson-Gilford progeria syndrome is a premature aging disease caused by LMNA gene mutation and the production of a truncated prelamin A protein "progerin" that elicits cellular and organismal toxicity. Progerin accumulates in the vasculature, being especially detrimental for vascular smooth muscle cells (VSMC). Vessel stiffening and aortic atherosclerosis in HGPS patients are accompanied by VSMC depletion in the medial layer, altered extracellular matrix (ECM), and thickening of the adventitial layer. Mechanisms whereby progerin causes massive VSMC loss and vessel alterations remain poorly understood. Mature VSMC retain phenotypic plasticity and can switch to a synthetic/proliferative phenotype. Here, we show that progerin expression in human and mouse VSMC causes a switch towards the synthetic phenotype. This switch elicits some level of replication stress in normal cells, which is exacerbated in the presence of progerin, leading to telomere fragility, genomic instability, and ultimately VSMC death. Calcitriol prevents replication stress, telomere fragility, and genomic instability, reducing VSMC death. In addition, RNA-seq analysis shows induction of a profibrotic and pro-inflammatory aging-associated secretory phenotype upon progerin expression in human primary VSMC. Our data suggest that phenotypic switch-induced replication stress might be an underlying cause of VSMC loss in progeria, which together with loss of contractile features and gain of profibrotic and pro-inflammatory signatures contribute to vascular stiffness in HGPS.
| S-EPMC9886737 | biostudies-literature
Project description:PARP1 regulates VSMC phenotypic switch and neointima via Myocardin
| PRJNA407927 | ENA
Project description:The premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A1. Progerin is also sporadically expressed in wild type cells and has been linked to physiological aging. HGPS cells exhibit extensive nuclear defects including abnormal chromatin structure and increased DNA damage. At the organismal level, HGPS affects several tissues particularly of mesenchymal origin. How the cellular defects of HGPS cells lead to the organismal defects has been unclear. To begin to unravel how progerin leads to disease phenotypes, we analyzed time-dependent changes in transcriptional profiles in response to progerin expression in a hTERT-immortalized skin fibroblast cell line expressing either GFP-progerin or the GFP-wt lamin A control Keywords: time course, cell line comparison
2008-02-09 | GSE10123 | GEO
Project description:Disassembly of the nuclear envelope is an essential feature of mammalian cell division controlled by the phosphoryaltion of lamins via cyclin dependent kinases. This process is affected in cells expressing progerin, a lamin A allele found in patients with Hutchinson-Gilford Progeria syndrome. Progerin can inhibit cell proliferation of both normal and tumor cells and this property is largely magnified if its phosphorylation at serine 22 is inhibited by a genetic mutation to generate S22A-progerin. Surprisingly, S22A-progerin acquires the ability to trigger cellular senescence in tumor cells with mutations in the p53 and RB tumor suppression pathways suggesting a novel pathway to control the growth of malignant tumors. We used microarrays to characterize the gene expression changes induced by the S22A-progerin in comparison with the wt-progerin in U-2 OS cell line. U-2 OS cells were infected with a retroviral vector that express S22A-progerin or wt-progerin. After 4 days of infection, RNA was extracted from three independents replicas of each condition. Total RNA was send to Genome Quebec service for hybridization with Affymetrix microarrays.
2014-03-01 | E-GEOD-51349 | biostudies-arrayexpress
Project description:Disassembly of the nuclear envelope is an essential feature of mammalian cell division controlled by the phosphoryaltion of lamins via cyclin dependent kinases. This process is affected in cells expressing progerin, a lamin A allele found in patients with Hutchinson-Gilford Progeria syndrome. Progerin can inhibit cell proliferation of both normal and tumor cells and this property is largely magnified if its phosphorylation at serine 22 is inhibited by a genetic mutation to generate S22A-progerin. Surprisingly, S22A-progerin acquires the ability to trigger cellular senescence in tumor cells with mutations in the p53 and RB tumor suppression pathways suggesting a novel pathway to control the growth of malignant tumors. We used microarrays to characterize the gene expression changes induced by the S22A-progerin in comparison with the wt-progerin in U-2 OS cell line.
2014-03-01 | GSE51349 | GEO
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, genetic premature aging disorder associated with severe atherosclerosis, often resulting in fatal heart attacks and strokes. Progerin, the mutant protein in HGPS, also is expressed in healthy individuals and may play a role in the development of atherosclerosis during physiologic aging. Here, we provide evidence for a primary involvement of vascular endothelium in the pathogenesis of accelerated atherosclerosis in HGPS. Expression of progerin in cultured human endothelial cells induces a dysfunctional phenotype, manifested by activation of multiple pro-inflammatory, pro-atherogenic genes. In particular, our data implicate endothelial-derived interleukin-1 (IL-1) as a key mediator of a pro-inflammatory vascular phenotype. Endothelial activation also is detectable in a mouse model of HGPS, and appears to be conveyed to neighboring vascular cells via autocrine and paracrine signaling. These new mechanistic insights into the vascular pathobiology of HGPS may have therapeutic implications for this disease. Genome-wide transcriptional profiling was carried out to assess functional phenotypic changes in endothelial cells (EC) as a result of progerin expression. Cultured EC were infected with an adenovirus expressing progerin (Ad-Progerin), and as a control, an adenovirus that did not express any construct (Ad-Null). Experiments were preformed with three different EC cultures.
2010-12-02 | E-GEOD-19270 | biostudies-arrayexpress
Project description:Vascular calcification is a hallmark of atherosclerosis and end-stage renal disease (ESRD). However, the molecular mechanism of vascular calcification is poorly understood. Diabetes mellitus is increasingly recognized as the most important cause for atherosclerosis and ESRD. Emerging evidence supports the concept that vascular calcification resembles the process of osteogenesis, in which the vascular smooth muscle cells (VSMC) undergo osteochondrogenic differentiation. Recently, we have established an in vitro calcification system with primary mouse VSMC. With the use of osteogenic stimuli, we induced trans-differentiation of primary mouse VSMC into bone-like cells. Interestingly stroptozotocin (STZ), O-GlcNAcase inhibitor and a drug that has been used to induce diabetes in mice, was able to induce calcification of VSMC and the expression of the osteogenic transcription factor Runx2, suggesting glycosylation may be involved in regulation of Runx2. We have reported an essential role of Runx2 in oxidative stress-induce VSMC calcification and have recently generated a tissue specific mouse with Runx2 ablation in smooth muscle cells. Therefore, we will use STZ and other relevant reagents in the glucose synthesis/metabolism pathways as stimuli for VSMC calcification to characterize the glycogene profiles during VSMC calcification. Results from VSMC of Runx2 knockout mice will be compared with those from control mice to determine the regulation of calcification-associated glycogenes by Runx2 in response to STZ. These studies will provide foundation for further mechanistic studies and may lead to identification of novel strategies and targets for diabetes-induced vascular calcification. To examine vascular smooth muscle cells (VSMC) under two conditions: 1) wild-type VSMC differentiated into bone-like cells with osteogenic media, 2) wild-type VSMC treated with STZ and osteogenic media
2011-09-05 | E-GEOD-31928 | biostudies-arrayexpress