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Cytosolic Hsp60 orchestrates the survival and inflammatory responses of vascular smooth muscle cells in injured aortic vessels by regulating NF-κB-dependent gene expression

ABSTRACT: Pro-inflammatory response of VSMCs is triggered by endothelial damage and a causative step for thrombosis and neointimal thickening in the arterial vessels. Therefore, we investigate a role of cytosolic Hsp60 as a novel pro-inflammatory mediator in VSMCs. Hsp60 was detected in the cytosol of VSMCs. The selective depletion of cytosolic Hsp60 in VSMCs reduced the IKK activation, repressed the induction of NF-κB-dependent pro-survival genes (MnSOD and Bfl-1/A1), and enhanced apoptotic death in response to TNF-α. Moreover, a quantitative RNA sequencing revealed that the expression of 75 genes among the 774 TNF-α-inducible genes was significantly reduced by the depletion of cytosolic Hsp60. In particular, the expression of pro-inflammatory cytokines/chemokines, such as CCL2, CCL20, and IL-6, was regulated by the cytosolic Hsp60 in VSMCs. Finally, the depletion of cytosolic Hsp60 markedly inhibited the neointimal thickening in the balloon-injured arterial vessels by inducing apoptotic cell death and inhibiting chemokine production. This study provides the first evidence that cytosolic Hsp60 could be a therapeutic target for preventing inflammation-driven VSMC hyperplasia in the injured vessels. Hsp60 normal vs knockout with TNF-alpha treatment

ORGANISM(S): Homo sapiens

SUBMITTER: Charny Park

PROVIDER: E-GEOD-65354 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Cytosolic Hsp60 orchestrates the survival and inflammatory responses of vascular smooth muscle cells in injured aortic vessels by regulating NF-κB-dependent gene expression

Project description:Pro-inflammatory response of VSMCs is triggered by endothelial damage and a causative step for thrombosis and neointimal thickening in the arterial vessels. Therefore, we investigate a role of cytosolic Hsp60 as a novel pro-inflammatory mediator in VSMCs. Hsp60 was detected in the cytosol of VSMCs. The selective depletion of cytosolic Hsp60 in VSMCs reduced the IKK activation, repressed the induction of NF-κB-dependent pro-survival genes (MnSOD and Bfl-1/A1), and enhanced apoptotic death in response to TNF-α. Moreover, a quantitative RNA sequencing revealed that the expression of 75 genes among the 774 TNF-α-inducible genes was significantly reduced by the depletion of cytosolic Hsp60. In particular, the expression of pro-inflammatory cytokines/chemokines, such as CCL2, CCL20, and IL-6, was regulated by the cytosolic Hsp60 in VSMCs. Finally, the depletion of cytosolic Hsp60 markedly inhibited the neointimal thickening in the balloon-injured arterial vessels by inducing apoptotic cell death and inhibiting chemokine production. This study provides the first evidence that cytosolic Hsp60 could be a therapeutic target for preventing inflammation-driven VSMC hyperplasia in the injured vessels.

2015-03-01 | GSE65354 | GEO

Gene expression profile of PTPN14 silence with PDGF-BB stimulation in HA-VSMCs

Project description:The moderate response of smooth muscle cells is beneficial to the repair of vascular injury, while the continuous exposure of intravascular growth factors, and other stimulating factors will cause the dysfunction of smooth muscle cells, leading to the pathological remodeling of blood vessels, which is called neointimal hyperplasia. The aim of this study is to investigate the biological function of PTPN14 in vascular smooth muscle cells (VSMCs) and the mechanism of PTPN14 in regulating neointimal hyperplasia.

2024-07-17 | GSE267140 | GEO

Mice VSMCs: Control vs. TNF-α cultured

Project description:Mice VSMCs: Control vs. TNF-α cultured

| PRJNA524301 | ENA

Mice VSMCs: Control vs. TNF-α cultured

Project description:Transcriptional profiling of mouse VSMCs comparing control with VSMCs cultured with TNF-α Apoptosis of vascular smooth muscle cells (VSMCs) is a process that regulates vessel remodeling in various cardiovascular diseases. The specific mechanisms that control VSMC apoptosis remain unclear. The present study aimed to investigate whether microRNA-494 (miR-494) is involved in regulating VSMC apoptosis and its underlying mechanisms. Cell death ELISA and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assays were used to detect apoptosis of murine VSMCs following stimulation with tumor necrosis factor(TNF-α). The results indicated that TNF-α-upregulated VSMC apoptosis in a dose-dependent manner. Microarray analysis was used to evaluate the expression profile of microRNAs following TNF-α-stimulation in murine VSMCs. The expression of miR-494 was downregulated, whereas B-cell lymphoma 2-like 11 (BCL2L11) protein expression levels were upregulated in VSMCs following treatment with TNF- . Luciferase reporter assays confirmed that BCL2L11 was a direct target of miR-494. Transfection with miR-494 mimics decreased VSMC apoptosis and downregulated BCL2L11 protein levels. Conversely, transfection with miR-494 inhibitors increased cell apoptosis and upregulated BCL2L11 protein levels, suggesting that miR-494 may function as an essential regulator of BCL2L11. The increase in apoptosis caused by miR-494 inhibitors was abolished in cells co-transfected with BCL2L11-targeting small interfering RNA. The findings of the present study revealed that miR-494 inhibited TNF-α-induced VSMC apoptosis by downregulating the expression of BCL2L11.

2019-02-28 | GSE127016 | GEO

MFAP4 is an integrin M-NM-1VM-NM-23/5 ligand involved in vascular remodeling

Project description:Arterial injury or occlusive arterial disease may stimulate healing responses, which when overexuberant, leads to restenosis of the injured vessel. This response is influenced by specific integrin signalling in vascular smooth muscle cells (VSMCs). Microfibril-associated protein 4 (MFAP4) colocates in blood vessels with elastic fibers. MFAP4 contains an N-terminal RGD-motiv, which is a potential integrin binding site. The role for MFAP4 in vascularproliferative disease is so far unknown and the subject for these investigations. Here we show that MFAP4 is expressed and secreted by VSMCs and binds elastin and collagen. MFAP4 mediated adhesion, and migration, and proliferation of VSMCs in an integrin M-NM-1VM-NM-23/5 dependent manner and the effects were inhibited by MFAP4 blocking antibodies. MFAP4 deficient mutant mice were generated and appeared with a normal cardiophysiological phenotype. When challenged by carotid artery ligation, the MFAP4 deficient mice had delayed neointimal formation and the compensatory outward remodeling of the vessel diameter and thus the vessel lumen was reduced. MFAP4 expression appeared unaffected by the induced pathology. HUMANE DATA This new MFAP4 mediated molecular mechanism for regulation of integrin M-NM-1VM-NM-23/5 signalling may have therapeutic implications in diseases where VSMC migration and proliferation are involved in the pathogenesis. For genome-wide expression analysis total RNA from heart of four male MFAP4-/- and four control mice was isolated using RNeasy Midi kit (Qiagen, Hilden, Germany). The cDNA microarrays were generated, hybridized and analysed as described (Horsch et al 2009). Two chip hybridizations were performed with total RNA for each individual mutant mouse against a reference RNA pool of the same organ.

2013-04-01 | E-GEOD-40480 | biostudies-arrayexpress

Single Cell Transcriptomic Analysis of Popliteal Lymphatic Vessels and Peripheral Veins with Smooth Muscle Cell Enrichment in TNF-Tg vs WT Mice

Project description:Lymphatic dysfunction exists in tumor necrosis factor transgenic (TNF-Tg) mice and rheumatoid arthritis (RA) patients. While joint-draining TNF-Tg popliteal lymphatic vessels (PLVs) have deficits in contractility during end-stage arthritis, the nature of lymphatic muscle cells (LMCs) and their TNF altered transcriptome remain unknown. Thus, we performed single-cell RNA-sequencing (scRNAseq) on TNF-Tg vs wild-type peripheral vasculature. We utilized strategic enrichment for smooth muscle cells using a Cspg4-Cre;tdTomato reporter model, and through post-hoc analysis we validated the ability to enrich for these tdTomato+ populations based on scatter alone. As such, we evaluated changes in LMC populations vs vascular smooth muscle cells (VSMCs), and dynamic changes in peri-vascular immune cell populations during chronic inflammatory-erosive arthritis.

2022-03-07 | GSE190999 | GEO

MFAP4 is an integrin αVβ3/5 ligand involved in vascular remodeling

Project description:Arterial injury or occlusive arterial disease may stimulate healing responses, which when overexuberant, leads to restenosis of the injured vessel. This response is influenced by specific integrin signalling in vascular smooth muscle cells (VSMCs). Microfibril-associated protein 4 (MFAP4) colocates in blood vessels with elastic fibers. MFAP4 contains an N-terminal RGD-motiv, which is a potential integrin binding site. The role for MFAP4 in vascularproliferative disease is so far unknown and the subject for these investigations. Here we show that MFAP4 is expressed and secreted by VSMCs and binds elastin and collagen. MFAP4 mediated adhesion, and migration, and proliferation of VSMCs in an integrin αVβ3/5 dependent manner and the effects were inhibited by MFAP4 blocking antibodies. MFAP4 deficient mutant mice were generated and appeared with a normal cardiophysiological phenotype. When challenged by carotid artery ligation, the MFAP4 deficient mice had delayed neointimal formation and the compensatory outward remodeling of the vessel diameter and thus the vessel lumen was reduced. MFAP4 expression appeared unaffected by the induced pathology. HUMANE DATA This new MFAP4 mediated molecular mechanism for regulation of integrin αVβ3/5 signalling may have therapeutic implications in diseases where VSMC migration and proliferation are involved in the pathogenesis.

2013-04-01 | GSE40480 | GEO

A Novel Hidden Protein p-414aa Encoded by circSETD2(14,15) Inhibits Vascular Remodeling

Project description:The phenotypic switching of vascular smooth muscle cells (VSMCs) leads to neointimal hyperplasia, which is the underlying cause of vascular remodeling diseases such as atherosclerosis and hypertension. Novel hidden proteins encoded by circular RNAs (circRNAs) play crucial roles in disease progression. Our study identified a new protein derived from a circRNA in VSMCs and demonstrated its potential role in regulating vascular remodeling. We discovered a novel hidden protein, p-414aa, encoded by circSETD2(14,15), which can inhibit vascular remodeling. Both circSETD2(14,15) and p-414aa may serve as potential therapeutic targets for vascular remodeling diseases. In this study, we demonstrated that the new protein p-414aa encoded by circSETD2(14,15) inhibits VSMC proliferation and neointimal hyperplasia through the HuR/C-FOS axis. In summary, our data provide a molecular framework for the phenotypic switching of vascular smooth muscle cells.

2024-11-13 | GSE281385 | GEO

Genetic ablation of TonEBP/NFAT5 in smooth muscle cells inhibits arterial remodeling

Project description:Chronic biomechanical stress elicits remodeling of the arterial wall and causes detrimental arterial stenosis and stiffening. In this context, molecular determinants controlling proliferation and stress responses of vascular smooth muscle cells (VSMCs) have been insufficiently studied. We identified the transcription factor ‘nuclear factor of activated T-cells 5’ (NFAT5) as crucial regulatory element of mechanical stress responses of VSMCs. The relevance of this observation for biomechanically induced arterial remodeling was investigated in mice upon SMC-specific knockdown of NFAT5. While blood pressure levels, vascular architecture and flow-induced collateral growth were not affected in these mice, both hypertension-mediated arterial thickening and muscularization of pulmonary arteries during pulmonary artery hypertension (PAH) were impaired. In all models, a decrease in VSMC proliferation was observed indicating that NFAT5 controls activation of VSMCs in the remodeling arterial wall. Mechanistically, mechanoactivation of VSMCs promotes nuclear translocation NFTA5c upon its phosphorylation at Y143 and dephosphorylation at S1197. As evidenced by transcriptome studies, loss of NFAT5 in mechanoactivated VSMCs impairs expression of gene products controlling cell cycle and transcription/translation. These findings identify NFAT5 as molecular determinant of VSMC responses to biomechanical stress and arterial thickening.

2018-08-10 | GSE106274 | GEO

Inhibition of PARP 1 Protects Against Hyperglycemic-induced Neointimal Hyperplasia by Upregulating TFPI-2 Activity

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

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