NEXN regulates vascular smooth muscle cells phenotypic switching and neointimal hyperplasia
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ABSTRACT:
PROVIDER: PRJNA1262900 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33568106_1.fastq.gz | Fastqsanger.gz | |||
| SRR33568106_2.fastq.gz | Fastqsanger.gz | |||
| SRR33568107_1.fastq.gz | Fastqsanger.gz | |||
| SRR33568107_2.fastq.gz | Fastqsanger.gz | |||
| SRR33568108_1.fastq.gz | Fastqsanger.gz |
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Project description:Vascular smooth muscle cells (VSMCs) exhibit significant heterogeneity and plasticity, enabling them to switch between contractile and synthetic states, which is crucial for vascular remodeling. NEXN has been identified as a high confidence gene associated with dilated cardiomyopathy (DCM). Existing evidence indicate NEXN is involved in phenotypic switching of VSMCs. However, a comprehensive understanding of the cell - specific roles and precise mechanisms of NEXN in vascular remodeling remains elusive. Using integrative transcriptomics analysis and smooth muscle specific lineage tracing mice, we demonstrate NEXN is highly expressed in VSMCs, and the expression of NEXN is significantly reduced during the phenotypic transformation of VSMCs and intimal hyperplasia induced by vascular injury. VSMC - specific NEXN deficiency promoted the phenotypic transition of VSMCs and exacerbated neointimal hyperplasia in mice following vascular injury. Mechanistically, we found NEXN primarily mediated VSMCs proliferation and phenotypic transition through endoplasmic reticulum (ER) stress and KLF4 signaling. Inhibiting ER stress ameliorated VSMCs phenotypic transition by reducing cell cycle activity and proliferation caused by NEXN deficiency. These findings indicate targeting NEXN could be explored as a promising therapeutic approach for proliferative arterial diseases.
2025-05-16 | GSE297149 | GEO
Project description:Platelet-derived growth factor (PDGF-BB) released from the injured intima induces the proliferation and migration of vascular smooth muscle cells (VSMCs), which is the key mechanism of neointimal hyperplasia. Zinc finger 36 (ZFP36), a widespread RNA-binding protein, is important for pathological processes in many diseases. In this study we investigated the role of ZFP36 in VSMCs proliferation, migration and neointimal hyperplasia in mice. We generated smooth muscle-specific Zfp36 knockout (Zfp36SMKO) mice, and established restenosis mouse models by ligation of left carotid artery in Zfp36SMKO mice. We showed that the expression levels of ZFP36 were significantly decreased in human atherosclerotic coronary arteries and murine injured carotid arteries compared with controls. Compared to control Zfp36fl/fl mice, Zfp36SMKO mice displayed accelerated neointimal hyperplasia. In cultured mouse VSMCs, PDGF-BB (20 ng/mL) significantly downregulated ZFP36 expression through KLF4 binding site in Zfp36 promoter. We revealed that ZFP36 could bind to the mRNA of cell migration-inducing protein (CEMIP) and promoted its degradation in VSMCs, thereby reducing the expression of CEMIP protein. Knockdown of Cemip inhibited VSMCs proliferation and migration induced by Zfp36 knockout, thereby suppressing neointimal hyperplasia in Zfp36SMKO mice. We conclude that vascular smooth muscle ZFP36 has a protective effect against neointimal hyperplasia by reducing CEMIP expression. ZFP36 is downregulated by vascular injury and PDGF-BB treatment, which promotes VSMCs proliferation and migration and neointima formation. The results suggest that targeting ZFP36 may represent a novel therapeutic strategy for preventing or treating neointimal hyperplasia and related cardiovascular diseases.
2025-05-29 | GSE286906 | GEO
Project description:BACKGROUND: Neointimal hyperplasia is the major cause of significant vascular complications following arterial interventions. Despite the advancements in strategies such as drug-eluting stents (DES) to minimize neointimal hyperplasia, achieving consistently effective long-term outcomes remains a challenge. Protein-protein interactions (PPIs) mediated by PDZ domains are essential for numerous biological processes. However, little is known about the role of PDZ proteins in neointima formation. This study aims to explore the role of TAX1BP3, a singular PDZ protein, in phenotypic switching of VSMCs and its implication in neointimal hyperplasia. METHODS: Subcellular localization of TAX1BP3 was assessed in isolated VSMCs or arteries obtained from mice with neointima formation. TAX1BP3 mutants were constructed to study the role of SUMOylation on TAX1BP3 nucleocytoplasmic shuttling. VSMC-specific Tax1bp3 knockout mice were generated to determine the relevant phenotypes in a carotid artery wire injury model. RNA sequencing, ATAC-sequencing, computational prediction of complex structures, and Co-immunoprecipitation (Co-IP) were performed to elucidate the underlying molecular mechanisms. AAV-mediated Tax1bp3 gene delivery and engineered AIENPs-TAX1BP3 were employed to investigate the potential translational relevance. RESULTS: TAX1BP3 exhibited dynamic nucleocytoplasmic shuttling during phenotypic switching of VSMCs. TAX1BP3 is SUMOylated at K116 and its SUMOylation is essential for maintaining the nuclear localization of TAX1BP3. Deficiency of TAX1BP3 facilitated the transition from a contractile to synthetic phenotype and aggravated neointima formation following vascular injury in mice. The integration of RNA sequencing and ATAC sequencing unveiled that TAX1BP3 primarily regulated the cell cycle progression and cell proliferation of VSMCs through YAP-TEAD transcription activity. The computational prediction of TAX1BP3/YAP1 complex structures and protein interaction related experiments revealed TAX1BP3 and TEAD1 compete for binding to YAP through its TEAD binding domain via a non-canonical PDZ manner. AAV-mediated Tax1bp3 gene delivery significantly attenuated post-injury neointima formation and the progression of atherosclerosis. AIENPs-TAX1BP3 administration effectively reduced VSMCs phenotypic switching and neointimal hyperplasia. CONCLUSIONS: These results demonstrated SUMOylation of TAX1BP3 at K116 enables its nucleocytoplasmic shuttling during phenotypic switching of VSMCs. TAX1BP3 competitively interacts with YAP-TEAD complex in a non-canonical PDZ manner and exerted its protective role in vascular neointimal hyperplasia primarily through the regulation of cell proliferation.
2025-07-01 | GSE297516 | GEO
Project description:Deletion of Smooth Muscle ZFP36 Promotes Neointimal Hyperplasia in Mice
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Project description:To investigate the function and potential mechanism of PARP-1 poly(ADP-ribose) polymerase 1 (PARP1) in diabetic neointimal hyperplasia. Type 1 diabetes mellitus was induced using streptozotocin (STZ) in wild-type mice and PARP1-/- mice, and ligation of the left carotid artery was performed to induce neointimal hyperplasia. Ligated carotid arteries from diabetic mice developed more extensive neointimal hyperplasia and showed greater proliferation and migration than arteries from nondiabetic mice. The augmented remodeling response was absent in diabetic mice deficient in PARP1. PARP1 deficiency reduces diabetic neointimal hyperplasia by upregulating tissue factor pathway inhibitor (TFPI)-2, which acted as a suppressor of vascular smooth muscle cell (VSMCs) proliferation and migration. The underlying mechanisms involve PARP1 that acts as a negative transcription factor by enhancing TFPI-2 promoter DNA methylation. Our studies demonstrated for the first time that Inhibition of PARP1 alleviates neointimal hyperplasia in diabetes by up-regulating TFPI-2 expression and blocking VSMC proliferation and migration. The development of PARP1 inhibitors might serve to limit mainly proliferative and migratory processes in restenosis-prone diabetic patients
2019-11-30 | GSE141193 | GEO
Project description:Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.
2022-11-09 | PXD038057 |
Project description:Affymetrix Mouse Gene 2.0 ST Gene Expression Microarrays were used to analyze differentially expressed genes after carotid artery ligation. The aim of this experiment was to detect genes regulated in Has3 deficient as compared to wildtype controls that might be involved in neointimal hyperplasia. Neointimal hyperplasia was induced in female Has3 deficient mice and wildtype controls by ligation of the left common carotid artery. Carotid transcriptome was analyzed 5 days after surgery in ligated and non-ligated carotid arteries.
2015-11-24 | E-GEOD-70410 | biostudies-arrayexpress
Project description:Fractalkine Antibody Attenuates Venous Neointimal Hyperplasia of Arteriovenous Fistula in Mice model
2021-09-15 | GSE161555 | GEO
Project description:Vascular smooth muscle cells (VSMCs) possess significant phenotypic plasticity, shifting between a contractile phenotype and a synthetic state for vascular repair/remodelling. Dysregulated VSMC transformation, marked by excessive proliferation and migration, primarily drives intimal hyperplasia. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in gene expression regulation; however, its impact on VSMC plasticity is not fully understood. This research investigates the alterations in m6A modification and its regulatory factors during VSMC phenotypic shifts and their influence on intimal hyperplasia. We demonstrate that METTL14, crucial for m6A deposition, significantly promotes VSMC dedifferentiation. METTL14 expression, initially negligible, is elevated in synthetic VSMC cultures, post-injury neointimal VSMCs, and human restenotic arteries. Reducing Mettl14 levels in mouse primary VSMCs decreases pro- synthetic genes, suppressing their proliferation and migration. m6A-RIP-seq profiling shows key VSMC gene networks undergo altered m6A regulation in Mettl14-deficient cells. Mettl14 enhances Klf4 and Serpine1 expression through increased m6A deposition. Local Mettl14 knockdown significantly curbs neointimal formation post-arterial injury, and reducing Mettl14 in hyperplastic arteries halts further neointimal development. We found that Mettl14 is a pivotal regulator of VSMC dedifferentiation, influencing Klf4- and Serpine1- mediated phenotypic conversion. Inhibiting Mettl14 is a viable strategy for preventing restenosis and halting restenotic occlusions
2025-03-17 | GSE291558 | GEO
Project description:Vascular smooth muscle cells (VSMCs) possess significant phenotypic plasticity, shifting between a contractile phenotype and a synthetic state for vascular repair/remodelling. Dysregulated VSMC transformation, marked by excessive proliferation and migration, primarily drives intimal hyperplasia. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in gene expression regulation; however, its impact on VSMC plasticity is not fully understood. This research investigates the alterations in m6A modification and its regulatory factors during VSMC phenotypic shifts and their influence on intimal hyperplasia. We demonstrate that METTL14, crucial for m6A deposition, significantly promotes VSMC dedifferentiation. METTL14 expression, initially negligible, is elevated in synthetic VSMC cultures, post-injury neointimal VSMCs, and human restenotic arteries. Reducing Mettl14 levels in mouse primary VSMCs decreases pro- synthetic genes, suppressing their proliferation and migration. m6A-RIP-seq profiling shows key VSMC gene networks undergo altered m6A regulation in Mettl14-deficient cells. Mettl14 enhances Klf4 and Serpine1 expression through increased m6A deposition. Local Mettl14 knockdown significantly curbs neointimal formation post-arterial injury, and reducing Mettl14 in hyperplastic arteries halts further neointimal development. We found that Mettl14 is a pivotal regulator of VSMC dedifferentiation, influencing Klf4- and Serpine1- mediated phenotypic conversion. Inhibiting Mettl14 is a viable strategy for preventing restenosis and halting restenotic occlusions
2025-03-17 | GSE291560 | GEO