Paraspeckle protein NONO attenuates vascular calcification by inhibiting BMP2 transcription
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252244 | GEO | 2024/01/10
REPOSITORIES: GEO
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2023-11-22 | GSE243752 | GEO
Project description:Background: Ectopic vascular calcifications represent a major clinical problem associated with cardiovascular disease and mortality. However, the mechanisms underlying pathological vascular calcifications are largely unknown hampering the development of therapies to tackle this life threatening medical condition. Results: In order to gain insight into the genes and mechanisms driving this pathological calcification process we analyzed the transcriptional profile of calcifying vascular smooth muscle cells (C-VSMCs). These profiles were compared to differentiating osteoblasts, cells that constitute their physiological calcification counterparts in the body. Overall the transcriptional program of C-VSMC and osteoblasts did not overlap. Several genes, some of them relevant for bone formation, were distinctly modulated by C-VSMCs which did not necessarily lose their smooth muscle cell markers while calcifying. Bioinformatics gene clustering and correlation analysis disclosed limited bone-related mechanisms being shared by two cell types. Extracellular matrix (ECM) and biomineralization genes represented common denominators between pathological vascular and physiological bone calcifications. These genes constitute the strongest link between these cells and represent potential drivers for their shared end-point phenotype. Conclusions: the analyses support the hypothesis that VSMC trans-differentiate into C-VSMCs keeping their own identity while using mechanisms that osteoblasts use to mineralize. The data provide novel insights into groups of genes and biological processes shared in MSC and VSMC osteogenic differentiation. The distinct gene regulation between C-VSMC and osteoblasts might hold clues to find cell-specific pathway modulations, opening the possibility to tackle undesired vascular calcifications without disturbing physiologic bone formation and vice versa. Total RNA obtained from hMSC and hVSMC cultured in osteogenic differentiation medium supplemented with 1.8 mM Ca2+ for 0, 2, 8, 12 or 25 days respectively. For each timepoint 3 replicates were used, with exception for day 0 where 4 replicates were collected.
2014-10-10 | E-GEOD-37558 | 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
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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2022-10-04 | PXD029632 | Pride
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