Prelamin A drives vascular calcification by reorganization of the epigenetic landscape to promote inflammaging
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ABSTRACT:
PROVIDER: PRJNA980697 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24843700.fastq.gz | Fastqsanger.gz | |||
| SRR24843701.fastq.gz | Fastqsanger.gz | |||
| SRR24843702.fastq.gz | Fastqsanger.gz | |||
| SRR24843703.fastq.gz | Fastqsanger.gz | |||
| SRR24843704.fastq.gz | Fastqsanger.gz |
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Project description:Background: Vascular calcification is a ubiquitous ageing pathology markedly accelerated in patients with metabolic disorders including diabetes and renal failure. Prelamin A is a biomarker of vascular ageing which accelerates vascular smooth muscle cell (VSMC) senescence and calcification. Using prelamin A as a model we explored the earliest events in VSMC ageing, focussing on the epigenetic landscape as an environmentally modifiable target. Methods: Adenoviral expression of prelamin A was used to induce VSMC ageing and epigenetic modifications were monitored using immunofluorescence and targeted PCR-arrays. Epigenetic findings were verified in vitro using drugs targeting epigenetic modifiers and in vivo using immunohistochemistry in human vessels from young, aged and calcified patients. Transcriptomics, ChIP-seq and antibody arrays were used to identify and verify gene targets impacted by changes in the epigenetic landscape and to monitor effects on inflammation, ageing indices and calcification. A novel mouse model of VSMC-specific inducible prelamin A expression was used to study epigenetic ageing in vivo and calcification was induced with vitamin D. Results: Prelamin A accumulation in VSMCs caused rapid global alterations in the repressive heterochromatin marks, H3K9me3 and H3K27me3 which coincided with downregulation of the epigenetic writers EZH2 and SUV39H1. These same epigenetic changes were recapitulated in primary human VSMCs induced to calcify in response to mineral dysregulation and in the calcified arteries of adults, and young children on dialysis. Global analysis of H3K9me3 and H3K27me3 marks in response to prelamin A expression showed deregulation of cross-talking NF-κB and HIPK2 stress response inflammatory pathways consistent with robust activation of a senescence associated secretory phenotype (SASP). Treatment of VSMCs with EZH2 and SUV39H1 inhibitors amplified the SASP and accelerated senescence and mineral deposition. Induction of prelamin A expression in VSMCs in mice induced rapid loss of heterochromatin which preceded DNA damage and senescence and coincided with early activation of SASP factors creating an environment permissive to calcification. Conclusions: Loss of heterochromatin is accelerated by metabolic disease and acts to promote VSMC inflammaging and a tissue microenvironment prone to calcification. Pre-senescent cells with an active SASP may be an early target for tackling vascular ageing pathologies. tackling vascular ageing pathologies.
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Project description:Vascular calcification contributes to the cardiovascular morbidity and mortality of chronic kidney disease (CKD), but there is no approved treatment for vascular calcification. In this study, we report the role of STING in vascular calcification. To further investigate the molecular mechanism by which STING participates in vascular calcification, we performed high-throughput RNA-seq to identify the target gene of STING.
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Project description:Vascular calcification contributes to high cardiovascular mortality in chronic kidney disease (CKD) patients. An association between the uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) and cardiovascular disease has been suggested. This study provides strong etiological evidence for indoxyl sulfate and p-cresyl sulfate as major contributors to vascular calcification in chronic kidney disease patients. Continuous exposure to indoxyl sulfate or p-cresyl sulfate in rats with chronic kidney disease promotes moderate to severe calcification in the aorta and peripheral vessels. Unbiased proteomic analyses of arterial samples coupled to functional bioinformatics annotation analysis revealed that calcification events were associated with acute phase response signaling, coagulation and glucometabolic signaling pathways, while escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Activation of inflammation and coagulation pathways in the arterial wall plays a pivotal role in toxin-induced calcification and strongly associates with hyperglycemia and insulin resistance. These findings reveal new perspectives to establish novel therapeutic targets to prevent, halt progression or cure vascular calcification.
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Project description:Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced polyubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhanced VC. HDAC1 protein, but not mRNA, was reduced in cell and animal calcification models and in human calcified coronary artery. In the calcification-provoking condition, proteasomal degradation of HDAC1 preceded VC. The calcification-provoking condition induced MDM2 E3 ligase, which then resulted in HDAC1 K74 polyubiquitination. Overexpression of MDM2 enhanced VC, whereas loss of MDM2 blunted it. Decoy peptides spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevented VC in vivo and in vitro. These results demonstrate a previously unknown ubiquitination pathway and suggest MDM2-mediated HDAC1 polyubiquitination as a new therapeutic target in VC. Calcification was induced in rat aorta vascular smooth muscle cells with inorganic phosphate (Pi). Total RNA were extracted from the cells 3 and 6 days later. mRNA profile of the sample was compared with normal control.
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Project description:In this study, we report the protective effect of β-hydroxybutyrate (BHB) on vascular calcification in chronic kidney disease (CKD). To further investigate the mechanism underpinning the protective effect of BHB on vascular calcification, we performed high-throughput RNA-seq to identify the target gene of BHB. Our data demonstrate that BHB supplementation inhibits vascular calcification in CKD via targeting HDAC9.
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Project description:Vascular calcification is a common and life-threatening complication in patients with chronic kidney disease, in which osteogenic differentiation of vascular smooth muscle cells (VSMCs) plays an essential role. Paraspeckle protein NONO is a multifunctional protein involved in many nuclear biological processes but its role in vascular calcification and osteogenic differentiation of VSMCs remains unclear.By RNA sequencing analysis in primary mouse VSMCs with or without NONO knockout, we observed significant changes of genes important in regulating vascular function and osteogenic differentiation of VSMCs.
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Project description:In this study, we repoort the protective effect of ursolic acid (UA) on vascular calcification in chronic kidney disease. To elucidate the molecular mechanism underlying the anti-vascular calcification effect of UA, we performed RNA-seq to identify the gene expresion under UA treatmment.
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Project description:Vascular calcification, the ectopic deposition of calcium in blood vessels, develops in association with various metabolic diseases and atherosclerosis. Because it often causes stiffness and remodeling of the blood vessels, vascular calcification increases morbidity and mortality. Both miRNA and mRNA microarrays (Series GSE74755) were performed with rat VSMCs and reciprocally regulated pairs of miRNA and mRNA were selected after bioinformatic analysis.
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Project description:Vascular Calcification (VC) is a life threatening cardiovascular complication that accounts for high death rates particularly in association with diabetes, atherosclerosis and Chronic Kidney Disease (CKD. during VC, Vascular Smooth Muscle Cells (VSMCs) undergo reprogramming into osteoblast-like cells in response to calcium and phosphate mineral imbalance in CKD patients. This osteogenic switch is driven by the expression of several bone markers such as Runt- related transcription factor 2 (Runx2), Alkaline Phosphatase (ALP), Osteopontin (OPN), Matrix-Gla Protein (MGP), Osteocalcin (OCN), Type I Collagen (COL1), and Bone Sialo Proteins (BSPs). Recent studies showed that VSMCs secrete heterogeneous populations of Extracellular Vesicles (EVs)11 that are enriched under physiological conditions by calcification inhibitors such as Fetuin-A and MGP12,13,14. Interestingly, under pathological conditions, secreted EVs have a pro-calcifying profile and thereby act as nucleating foci for hydroxyapatite crystallization and propagation11,15. Electron Microscopy based studies revealed that EVs were embedded between collagen and elastin fibrils of arterial walls suggesting that calcification can be initiated through the EVs’ direct physical interaction with them13,16. We previously showed that a specific oligogalacturonic acid with a degree of polymerization of 8 (DP8) was able to inhibit vascular calcification. This inhibition was partly due to a decrease of osteogenic markers’s expression but also to the masking of a consensus sequence found in COL1 i.e. GFOGER sequence, thus preventing EVs from binding to COL1. Although the use of DP8 in-vivo seems to be compromised due to probable enzymatic digestion, these results suggested that the inhibition of VSMCs’ osteogenic switch and the prevention of EVs-COL1 interaction could represent new potential therapeutic targets for inhibiting VC17. Since we have already showed that the triple-helical GFOGER consensus sequence forms a preferential binding site for EVs17, we thereby chemically synthesized a GFOGER peptide in order to determine its ability to inhibit VC on VSMCs and on an aortic ring ex-vivo model. We also aim to decipher the mechanisms of inhibition by investigating the osteogenic markers’ expression as well as the protein content of secreted EVs in the presence of the GFOGER peptide.
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Project description:Role of EVs in inflammation propagation and oxidative stress during vascular calcification
2022-05-19 | PXD029441 | Pride