MicroRNA expression profile in vascular smooth muscle cells (VSMCs) after inducing calcification
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ABSTRACT:
PROVIDER: PRJNA540465 | ENA |
REPOSITORIES: ENA
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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.
2019-12-31 | GSE130486 | GEO
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.
2015-11-07 | E-GEOD-74755 | biostudies-arrayexpress
Project description:Vascular calcification (VC) is a strong predictor of cardiovascular risk, particularly in chronic kidney disease (CKD) patients, associated with increased vascular stiffness, pulse pressure, left ventricular hypertrophy and atherosclerotic plaque burden [1]. VC is currently accepted as a highly controlled multifactorial process, where the release of extracellular vesicles (EVs) with calcification capacity plays an essential role in mediating cell-induced matrix mineralization [2]. Still, questions considering mechanisms of EVs deposition in the extracellular space, and its relationship with vesicle origin, loading, calcifying capacity and role in intercellular communication remain elusive. In this work we established a proteomic approach to characterize extracellular matrix (ECM)-deposited and cell media (CM) released EVs, from an in vitro model of VC consisting of primary vascular smooth muscle cells (VSMCs), bringing new knowledge into their specific characteristics and cargo.
2025-05-06 | PXD044045 | Pride
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.
2024-01-10 | GSE252244 | GEO
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.
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Project description:SGLT-2 inhibitors, such as empagliflozin, have been shown to reduce the occurrence of cardiovascular events and delay the progression of atherosclerosis. However, its role in atherosclerotic calcification remains unclear. In this research, ApoE-/- mice were fed with western diet and empagliflozin was added to the drinking water for 24 weeks. Empagliflozin treatment significantly alleviated arterial calcification assessed by alizarin red and von kossa staining in aortic roots and reduced the lipid levels, while had little effect on body weight and blood glucose levels in ApoE-/- mice. In vitro studies, empagliflozin significantly inhibits calcification of primary vascular smooth muscle cells (VSMCs) and aortic rings induced by osteogenic media (OM) or inorganic phosphorus (Pi). RNA sequencing of VSMCs cultured in OM with or without empagliflozin showed that empagliflozin negatively regulated the osteogenic differentiation of VSMCs. And further studies confirmed that empagliflozin significantly inhibited osteogenic differentiation of VSMCs via qRT-PCR. Our study demonstrates that empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of VSMCs, which addressed a critical need for the discovery of a drug-based therapeutic approach in the treatment of atherosclerotic calcification.
2023-11-22 | GSE243752 | GEO
Project description:Cardiovascular diseases often manifest with vascular calcification. Vascular calcification is an active process orchestrated by contractile vascular smooth muscle cell (VSMC) phenotypic switch to an osteoblast-like cell. Here, we identified that the DNA demethylase, Tet2 (Ten-eleven translation 2), safeguards VSMCs from transitioning into the osteogenic lineage and loss of Tet2 promotes development and progression of vascular calcification. Tet2 was among the most significantly downregulated epigenetic markers in calcified aortas. VSMC-specific loss of Tet2 promoted VSMC osteogenic differentiation and enhanced vascular calcification as evidenced histologically, molecularly, and hemodynamically. In vivo studies further indicated that Tet2 inhibits calcification-associated VSMC apoptosis and medial thinning. Notably, calcified regions were enriched in a Trem2hi (triggered receptor expressed on myeloid cells 2) macrophage subpopulation. Intervention studies using high-dose ascorbate to enhance Tet2 enzymatic activity resulted in significantly reduced medial aortic calcification and improved aortic structural integrity in mice. Ascorbate treatment in human aorta organ cultures was sufficient to reduce calcification development in diseased tissues, and restore contractile properties to the calcified aorta. This study highlights the potential clinical impact of modulating Tet2 activity in managing cardiovascular disorders associated with vascular calcification.
2025-07-01 | GSE294266 | GEO
Project description:Hyperglycemia accelerates calcification of atherosclerotic plaques in diabetic patients, and the prolonged accumulation of advanced glycation end products (AGEs) induced by hyperglycemia may be closely related to the pathogenesis of aortic calcification. However, the mechanisms underlying this association remain unclear. In the current study, we investigated the role of vascular smooth muscle cell nuclear factor 90/110 (NF90/110) in mediating AGEs accumulation and accelerating diabetic atherosclerotic calcification. Using vascular smooth muscle cells (VSMCs), human samples, and mouse models, we found that hyperglycemia-mediated AGEs markedly increased VSMC NF90/110 activation both in human and mouse atherosclerotic calcified tissues with diabetes. Silencing of NF90/110 in vitro and genetic deletion of VSMC NF90/110 in mice decreased obviously AGEs-induced arteriosclerotic calcification. Mechanistically, AGEs increased the activity of NF90, which then enhanced ubiquitination and degradation of AGE receptor 1 (AGER1) by stabilizing the mRNA of E3 ubiquitin ligase, F-box, and WD repeat domain 7 (FBXW7), thus causing the accumulation of more AGEs. Furthermore, AGEs accumulation accelerated diabetic atherosclerotic calcification by inducing VSMC phenotypic changes to osteoblast-like cells, apoptosis, and matrix vesicle release. Collectively, our study demonstrated the effects of VSMC NF90 in mediating the metabolic imbalance of AGEs to accelerate diabetic arteriosclerotic calcification. These novel findings elucidate a pivotal mechanism underlying AGE-induced diabetic atherosclerotic calcification and provide a framework for potential interventions against diabetic vascular complications.
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Project description:Vascular calcification, a key risk factor for cardiovascular diseases, is driven by the phenotypic transition of vascular smooth muscle cells (VSMCs) from a contractile to an osteogenic phenotype. NEXN, a protein highly associated with heart function, has also been implicated as a potential susceptibility factor in the development of coronary artery disease, but its role in the progression of vascular calcification remains unclear. In this study, multi-transcriptomics analysis and various animal models were used to explore the cell-specific roles and molecular mechanisms of NEXN in vascular calcification. VSMC-specific NEXN knockout exacerbated calcification, while NEXN overexpression alleviated it. NEXN was shown to interact with SERCA2, enhancing its SUMOylation, stability, and function, thereby protecting against calcification. These findings suggest that NEXN modulates vascular calcification through SERCA2 stabilization, offering potential therapeutic strategies by targeting NEXN-SERCA2 interactions or enhancing SERCA2 SUMOylation to prevent vascular calcification and its complications.
2025-06-04 | GSE297578 | GEO
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.
2020-10-23 | PXD018169 | Pride