Molecular mechanism of calcification in vascular smooth muscle cells regulated by Shox2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1108163 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Vascular calcification is one of the most common cardiovascular complications in patients with chronic kidney disease (CKD) and contributes to subsequent cardiovascular mortality. However, the precise mechanisms underpinning vascular calcification are not fully understood. In the present study, we report the role of Shox2 in vascular calcification. To further explore the molecular mechanism by which Shox2 regulates vascular calcification, we performed high-throughput RNA-seq to identify the target gene of Shox2.
2025-07-10 | GSE266637 | 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: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: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
Project description:To study the underlying molecular mechanisms driving vascular calcification, we analyzed the transcriptome of calcium-phosphate calcified human coronary aortic smooth muscle cells cultured with zero, low, and high glucose for 3 days.
2025-07-16 | GSE283693 | GEO
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: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.
2024-04-02 | GSE253682 | GEO
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 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: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