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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65354 | GEO | 2015/03/01

SECONDARY ACCESSION(S): PRJNA273756

REPOSITORIES: GEO

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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. Hsp60 normal vs knockout with TNF-alpha treatment

2015-03-01 | E-GEOD-65354 | biostudies-arrayexpress

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

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

miRNA expression profile in rat carotid artery balloon injury model

Project description:The proliferation and remodeling of vascular smooth muscle cells (VSMCs) is an important pathological event in atherosclerosis and restenosis. Here we report that microRNA-132 (miR-132) blocks vascular smooth muscle cells (VSMC) proliferation by inhibiting the expression of LRRFIP1 [leucine-rich repeat (in Flightless 1) interacting protein-1]. MicroRNA microarray revealed that miR-132 was upregulated in the rat carotid artery after catheter injury, which was further confirmed by quantitative real-time RT-PCR. Transfection of an miR-132 mimic significantly inhibited the proliferation of VSMCs, whereas transfection of an miR-132 antagomir increased it. Bioinformatics showed that LRRFIP1 is a target candidate of miR-132. miR-132 down-regulated luciferase activity driven by a vector containing the 3’-untranslated region of Lrrfip1 in a sequence-specific manner. LRRFIP1 induced VSMC proliferation. Immunohistochemical analysis revealed that Lrrfip1 was clearly expressed along with the basal laminar area of smooth muscle, and its expression pattern was disrupted 7 days after arterial injury LRRFIP1 mRNA was decreased 14 days after injury. Delivery of miR-132 to rat carotid artery attenuated neointimal proliferation in carotid artery injury models. Our results suggest that miR-132 is a novel regulator of VSMC proliferation that represses neointimal formation by inhibiting LRRFIP1 expression. Balloon injury was induced in the carotid arteries of male Sprague–Dawley rats weighing approximately 250 g. Total RNA were extracted from the arterial sections after 10 days. MicroRNA profile of the sample was compared with non-injured control.

2013-04-23 | E-GEOD-45433 | biostudies-arrayexpress

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

Homo sapiens

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

| PRJNA273756 | ENA

miRNA expression profile in rat carotid artery balloon injury model

2013-04-23 | GSE45433 | GEO

Balloon injury-induced gene expression in common carotid arteries of wistar rat

Project description:The whole rat genome microarray expression profiling of carotid artery specimen was emplyed to identify the gene expression profile before and after balloon injury. In our study, the neointimal formation of carotid arteries was apparent at day 7 and markedly increased at day 21 after balloon injury. In order to investigate the underlying mechanism of neointimal formationin in injured carotid arteries, all genes involved in signaling pathways whose expression was altered 2-fold in injured carotid arteries at day 7 and day 21 as compared to uninjured arteries were filtered out. Expression of four genes (TLR4, IRAK1, IκBα, IL-1β) from TLR signaling pathway was quantified in the same RNA samples by quantitative real-time PCR, conforming that TLR signaling pathway participated in neointimal formation of carotid arteries after balloon injury.

2013-06-29 | GSE48279 | GEO

Balloon injury-induced gene expression in common carotid arteries of wistar rat

Project description:The whole rat genome microarray expression profiling of carotid artery specimen was emplyed to identify the gene expression profile before and after balloon injury. In our study, the neointimal formation of carotid arteries was apparent at day 7 and markedly increased at day 21 after balloon injury. In order to investigate the underlying mechanism of neointimal formationin in injured carotid arteries, all genes involved in signaling pathways whose expression was altered 2-fold in injured carotid arteries at day 7 and day 21 as compared to uninjured arteries were filtered out. Expression of four genes (TLR4, IRAK1, IM-NM-:BM-NM-1, IL-1M-NM-2) from TLR signaling pathway was quantified in the same RNA samples by quantitative real-time PCR, conforming that TLR signaling pathway participated in neointimal formation of carotid arteries after balloon injury. Balloon injury-induced gene expression in wistar rat was measured at day 7 and day 21 after balloon injury as compared with uninjured arteries. Two independent experiments were performed at each time (uninjured, day 7 or day 21) using different wistar rats for each experiment.

2013-06-29 | E-GEOD-48279 | biostudies-arrayexpress

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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