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Endothelin-1 driven proliferation of PASMC is c-fos dependent

ABSTRACT: Background: Pulmonary hypertension is a rare disease characterized by pulmonary artery smooth muscle cell (PASMC) proliferation leading to vascularremodeling. Multiple factors have been associated with the vessel wall thickening. However, the responsible mechanisms are not fully understood. Aim: In this study we aim to decipher the role ofc-fos and c-jun transcription factors in the vascular remodeling process. Methods and Results: Expression and immunohistochemical analyses revealed high expression of c-fos and c-jun transcription factors in the vessel wall of lungs from human IPAH samples, hypoxia exposed mice and monocrotaline treated rats. Microarray study from hypoxic lung homogenates revealed MAP kinase asthe most differentially regulated pathway. Additionally, ET-1 and CTGF were the most up-regulated genes. Consequently, ET-1 but not CTGF stimulation of human PASMCs increased DNA synthesis and expression of proliferative markers such as Ki67 and cell cycle regulator, cyclin D1. Moreover, ET-1 treatment elevated ERK-dependent c-fos expression and phosphorylation of c-fos and c-jun. Silencing of c-fos with siRNA abrogated the ET-1-induced proliferation of PASMC. Conclusion: This finding shed light on the involvement of c-fos/c-jun in vascular remodeling as well as on the molecular mechanisms regulating the proliferative response of PASMCs to ET-1.

ORGANISM(S): Mus musculus

PROVIDER: GSE56698 | GEO | 2014/04/11

SECONDARY ACCESSION(S): PRJNA244323

REPOSITORIES: GEO

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Endothelin-1 driven proliferation of PASMC is c-fos dependent

Project description:Background: Pulmonary hypertension is a rare disease characterized by pulmonary artery smooth muscle cell (PASMC) proliferation leading to vascularremodeling. Multiple factors have been associated with the vessel wall thickening. However, the responsible mechanisms are not fully understood. Aim: In this study we aim to decipher the role ofc-fos and c-jun transcription factors in the vascular remodeling process. Methods and Results: Expression and immunohistochemical analyses revealed high expression of c-fos and c-jun transcription factors in the vessel wall of lungs from human IPAH samples, hypoxia exposed mice and monocrotaline treated rats. Microarray study from hypoxic lung homogenates revealed MAP kinase asthe most differentially regulated pathway. Additionally, ET-1 and CTGF were the most up-regulated genes. Consequently, ET-1 but not CTGF stimulation of human PASMCs increased DNA synthesis and expression of proliferative markers such as Ki67 and cell cycle regulator, cyclin D1. Moreover, ET-1 treatment elevated ERK-dependent c-fos expression and phosphorylation of c-fos and c-jun. Silencing of c-fos with siRNA abrogated the ET-1-induced proliferation of PASMC. Conclusion: This finding shed light on the involvement of c-fos/c-jun in vascular remodeling as well as on the molecular mechanisms regulating the proliferative response of PASMCs to ET-1. 36 mice were divided into 2 groups and kept either under normoxic (Nox) or under hypoxic conditions (Hox.3h). RNA from 3 animals was pooled to get 6 pools per group. Each pool was subjected to microarray hybridization (Nox vs. Hox.3h) in a balanced dye-swap design, giving a total of 6 dual-color hybridizations.

2014-04-11 | E-GEOD-56698 | biostudies-arrayexpress

Differential Gene Expression Profiles of PASMCs Induced by Quercetin under Hypoxia

Project description:As the critical step of pathogenesis during hypoxic pulmonary arterial hypertension (PAH) vascular remodeling is closely associated with pulmonary arterial smooth muscle cell (PASMC) alterations induced by hypoxia that include persistent vasoconstriction, abnormal proliferation and PASMC resistance to apoptosis. Quercetin is a flavonoid compound extracted from green plants that inhibits proliferation, induces apoptosis, arrests the cell cycle, and rescues the constriction of PASMCs, but the underlying mechanisms remain poorly understood. In this study, we used a commercial Agilent Whole Rat Genome Oligo Microarray to determine the overall transcriptional response of PASMCs in response to exposure to hypoxia and the optimal concentration of quercetin. Hypoxia induced the upregulation of 1694 genes and the downregulation of 2091 genes compared with the normoxia group. Quercetin treatment resulted in 1790 upregulated genes and 1450 downregulated genes. Quercetin is known to cause differential expression of several of these genes that are known to promote proliferation, induce apoptosis (Cycs, Ppp3ca, Prkar2b, Akt3, Ppp3cc, Il1rap, Ntrk1), arrest the cell cycle (Chek2, Cdkn1c, Gadd45b, Stag2, Anapc7, Orc1, Ccne1, Myc3, Skp1, Espl1, Cdc45, Mcm4), and rescue PASMC constriction (Ramp1, Ramp3, Adcy5, Gnas, Prkcd, Itpr3, Adra1d, Calm1, Npr1, Avpr1a, Ednra, Adcy8). Real-time quantitative RT-PCR was performed to verify the microarray results. In conclusion, quercetin altered the expression profile of many genes regulated by hypoxia in PASMCs, which helps to further explore the mechanism of the effects of quercetin treatment on hypoxic PAH.

2015-08-20 | GSE72181 | GEO

Anti-proliferative effect of selexipag active metabolite MRE-269 on pulmonary arterial smooth muscle cells from patients with chronic thromboembolic pulmonary hypertension

Project description:Chronic thromboembolic pulmonary hypertension (CTEPH) is a group 4 pulmonary hypertension (PH) characterized by non-resolving thromboembolism in the central pulmonary artery and vascular occlusion in the proximal and distal pulmonary artery. Medical therapy is chosen for patients who are ineligible for pulmonary endarterectomy or balloon pulmonary angioplasty or who have symptomatic residual PH after surgery or intervention. Selexipag, an oral prostacyclin receptor agonist and potent vasodilator, was approved for CTEPH in Japan in 2021. To evaluate the pharmacological effect of selexipag on vascular occlusion in CTEPH, we examined how its active metabolite MRE-269 affects platelet-derived growth factor-stimulated pulmonary arterial smooth muscle cells (PASMCs) from CTEPH patients. MRE-269 showed a more potent anti-proliferative effect on PASMCs from CTEPH patients than on those from normal subjects. DNA-binding protein inhibitor genes ID1 and ID3 were found by RNA sequencing and real-time quantitative polymerase chain reaction to be expressed at lower levels in PASMCs from CTEPH patients than in those from normal subjects and were upregulated by MRE-269 treatment. ID1 and ID3 upregulation by MRE-269 was blocked by co-incubation with a prostacyclin receptor antagonist, and ID1 knockdown by small interfering RNA transfection attenuated the anti-proliferative effect of MRE-269. ID signaling may be involved in the anti-proliferative effect of MRE-269 on PASMCs. This is the first study to demonstrate the pharmacological effects on PASMCs from CTEPH patients of a drug approved for the treatment of CTEPH. Both the vasodilatory and the anti-proliferative effect of MRE-269 may contribute to the efficacy of selexipag in CTEPH.

2022-12-27 | GSE221511 | GEO

Transcription profiling of human normal subjects and IPAH patients to examine the effect of BMP-2 on pulmonary artery smooth muscle cells

Project description:Bone morphogenetic proteins (BMP) inhibit proliferation and induce apoptosis in pulmonary artery smooth muscle cells (PASMC) from normal subjects. Dysfunction of BMP signaling due to mutations in and/or downregulation of BMP receptors has been implicated in idiopathic pulmonary arterial hypertension (IPAH). We examined whether BMP differentially regulates gene expression in PASMC from normal subjects and IPAH patients using the Affymetrix microarray analysis. BMP-2 treatment (200 nM for 24 hrs) altered expression levels of 6,206 genes in normal and IPAH PASMC. 1,063 of these genes were regulated oppositely by BMP-2: 523 genes were downregulated by BMP-2 in normal PASMC but upregulated in IPAH PASMC, whereas 540 genes were upregulated by BMP-2 in normal PASMC but downregulated in IPAH PASMC. The divergent effects of BMP-2 on gene expression profiles indicate that PASMC may undergo significant phenotypic changes in IPAH patients during development of the disease. The transition of the antiproliferative effect of BMP-2 in normal PASMC to its proliferative effect in IPAH patients is attributed potentially to its differential effect on expression patterns of various genes that are involved in cell proliferation and apoptosis. Among the 6206 BMP-2-sensitive genes, there are more than 1800 genes whose expression levels were negatively (with a correlation coefficient, r, < -0.9) or positively (with r > +0.9) correlated with the pulmonary arterial pressure. These results suggest that BMP-mediated gene regulation is significantly altered in PASMC from IPAH patients and mRNA expression changes in BMP-regulated genes may be involved in the development of IPAH.

2007-09-07 | E-GEOD-2559 | biostudies-arrayexpress

Next Generation Sequencing of Wild Type and CMG2-/- Rat Lung Transcriptomes

Project description:Purpose:Pulmonary arterial hypertension secondary to congenital heart disease (CHD-PAH) with systemic-to-pulmonary shunt is characterized by proliferative vascular remodeling. Capillary morphogenesis gene-2 (CMG2) exhibits roles in cell proliferation and apoptosis. The purpose of this study was to determine the possible roles of CMG2 in the pathogenesis of systemic-to-pulmonary shunt induced PAH. Methods Lung tissue sections from CHD-PAH patients, systemic-to-pulmonary shunt induced PAH rat model, CMG2-/- rats, and PASMCs were used. Immunohistochemistry, real time polymerase chain reaction, Western blot, proliferation, apoptosis, and next generation sequencing (NGS) were performed in this study. Results CMG2 expression was reduced in lung tissues and pulmonary arterioles from Eisenmenger’s syndrome patient and rats with systemic-to-pulmonary shunt induced PAH. CMG2-/- rats exhibited heavier PAH and pulmonary vascular remodeling following exposure to systemic-to-pulmonary shunt for 8 weeks. Over-expression of CMG2 in cultured human PASMCs inhibited cell proliferation and promoted apoptosis, while knockdown of CMG2 promoted cell proliferation and inhibited apoptosis. A total of 1319 genes were found to be dysregulated in CMG2-/- rat lungs as detected by NGS. Biological processes influenced by these differentially expressed genes include regulation of blood vessel diameter, vasoconstriction, regulation of blood vessel size, vascular process in circulatory system, etc., and the most prominent pathway regulated is PI3K-Akt signaling pathway. Conclusion Our work identifies a novel role for CMG2 in systemic-to-pulmonary shunt induced PAH based on the findings that CMG2 deficiency could exacerbate systemic-to- pulmonary shunt induced vascular remodeling in the development of PAH. CMG2 may be a potential target for CHD-PAH treatment.

2022-12-13 | GSE142118 | GEO

Murine pulmonary arterial smooth muscle cells: Wild-type vs. NOX1 deficiency (miRNA profiling)

Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of ?-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. microRNA expression profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed. Pulmonary arterial smooth muscle cells were harvested form 3 mice.

2014-01-22 | E-GEOD-42015 | biostudies-arrayexpress

Murine pulmonary arterial smooth muscle cells: Wild-type vs. NOX1 deficiency (mRNA profiling)

Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of α-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. Transcriptional profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed. Pulmonary arterial smooth muscle cells were harvested from 3 mice.

2014-01-22 | E-GEOD-42014 | biostudies-arrayexpress

Implication of EZH2 in the hyper-proliferative and apoptosis-resistant phenotype of pulmonary artery smooth muscle cells in PAH: a transcriptomic and proteomic approach

Project description:The aim of this study was to determine whether EZH2 represents a new factor critically involved in the cancer-like phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and TCA cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.

2021-04-14 | GSE166996 | GEO

Effect of BMP-2 on Pulmonary Artery Smooth Muscle Cells from Patients with Idiopathic Pulmonary Arterial Hypertension

Project description:Bone morphogenetic proteins (BMP) inhibit proliferation and induce apoptosis in pulmonary artery smooth muscle cells (PASMC) from normal subjects. Dysfunction of BMP signaling due to mutations in and/or downregulation of BMP receptors has been implicated in idiopathic pulmonary arterial hypertension (IPAH). We examined whether BMP differentially regulates gene expression in PASMC from normal subjects and IPAH patients using the Affymetrix microarray analysis. BMP-2 treatment (200 nM for 24 hrs) altered expression levels of 6,206 genes in normal and IPAH PASMC. 1,063 of these genes were regulated oppositely by BMP-2: 523 genes were downregulated by BMP-2 in normal PASMC but upregulated in IPAH PASMC, whereas 540 genes were upregulated by BMP-2 in normal PASMC but downregulated in IPAH PASMC. The divergent effects of BMP-2 on gene expression profiles indicate that PASMC may undergo significant phenotypic changes in IPAH patients during development of the disease. The transition of the antiproliferative effect of BMP-2 in normal PASMC to its proliferative effect in IPAH patients is attributed potentially to its differential effect on expression patterns of various genes that are involved in cell proliferation and apoptosis. Among the 6206 BMP-2-sensitive genes, there are more than 1800 genes whose expression levels were negatively (with a correlation coefficient, r, < –0.9) or positively (with r > +0.9) correlated with the pulmonary arterial pressure. These results suggest that BMP-mediated gene regulation is significantly altered in PASMC from IPAH patients and mRNA expression changes in BMP-regulated genes may be involved in the development of IPAH. Keywords = bone morphogenetic receptor protein Keywords = idiopathic pulmonary arterial hypertension Keywords = transcription factor Keywords = gene expression profile Keywords: other

2005-10-21 | GSE2559 | GEO

Murine pulmonary arterial smooth muscle cells: Wild-type vs. NOX1 deficiency (miRNA profiling)

Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of α-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. microRNA expression profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed.

2014-01-22 | GSE42015 | GEO

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