TAX1BP3 is a SUMOylated Nucleocytoplasmic Shuttling Protein and Protects Against Vascular Neointimal Hyperplasia
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PROVIDER: PRJNA1265121 | ENA |
REPOSITORIES: ENA
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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: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: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.
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Project description:Fractalkine Antibody Attenuates Venous Neointimal Hyperplasia of Arteriovenous Fistula in Mice model
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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: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.
2015-11-24 | GSE70410 | GEO
Project description:1α,25-Dihydroxyvitamin D3 encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas
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Project description:Biological oscillations are observed at many levels of cellular organization. In the social amoebae Dictyostelium discoideum, starvation-triggered multicellular development is organized by periodic cAMP waves, which provide both chemoattractant gradients and developmental signals. We report that GtaC, a GATA transcription factor, exhibits rapid nucleocytoplasmic shuttling in response to cAMP waves. This behavior requires coordinated action of a nuclear localization signal and reversible G protein-coupled receptor (GPCR)-mediated phosphorylation. While both are required for developmental gene expression, receptor occupancy promotes nuclear exit of GtaC, which leads to a transient burst of transcription at each cAMP cycle. We demonstrate that this biological circuit, like an M-bM-^@M-^\edge triggerM-bM-^@M-^], filters out high frequency signals and counts those admitted, thereby enabling cells to modulate gene expression according to the dynamic pattern of the external stimuli. Transcriptional profiling during early development of wild-type, gtaC, GFP-GtaC/gtaC, and NLSex-GFP-GtaC/gtaC strains
2014-04-15 | E-GEOD-54866 | biostudies-arrayexpress
Project description:Biological oscillations are observed at many levels of cellular organization. In the social amoebae Dictyostelium discoideum, starvation-triggered multicellular development is organized by periodic cAMP waves, which provide both chemoattractant gradients and developmental signals. We report that GtaC, a GATA transcription factor, exhibits rapid nucleocytoplasmic shuttling in response to cAMP waves. This behavior requires coordinated action of a nuclear localization signal and reversible G protein-coupled receptor (GPCR)-mediated phosphorylation. While both are required for developmental gene expression, receptor occupancy promotes nuclear exit of GtaC, which leads to a transient burst of transcription at each cAMP cycle. We demonstrate that this biological circuit, like an “edge trigger”, filters out high frequency signals and counts those admitted, thereby enabling cells to modulate gene expression according to the dynamic pattern of the external stimuli.
2014-04-15 | GSE54866 | GEO
Project description:Deletion of Smooth Muscle ZFP36 Promotes Neointimal Hyperplasia in Mice
| PRJNA1210534 | ENA