Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA262501 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Purpose: Guided by an in silico combination of microRNA (miRNA) target prediction, analysis of transcriptomic changes in 137 human diseases, and advanced gene network modeling, we predicted the miR-130/301 family of miRNAs as a shared regulator of a fibrotic gene network across human diseases, thus orchestrating broad control over disease manifestation. The goals of this study are to compare the lung mRNA profile of mouse model of Pulmonary hypertension, one of the most fibrotic pathology uncovered by our in silico prediction, treated with an inhibitor of miR-130/301 (Short-130) to mice treated with a control inhibitor (Short-NC). Methods: Eight-week-old mice (C57BL/6) were injected with SU5416 (20 mg/kg/dose; Sigma-Aldrich), followed by exposure to normobaric hypoxia (10% O2; OxyCycler chamber, Biospherix Ltd.) for 2 weeks. After 2 weeks and confirmation of PH development in 5 mice (right heart catheterization), mice were further treated with 3 intrapharyngeal injections (every 4 days) of control or miR-130/301 shortmer oligonucleotides, designed as fully modified antisense oligonucleotides complementary to the seed sequence of the miR-130/301 miRNA family (10 mg/kg/dose; Regulus). Specifically, the control and miR-130/301 shortmer oligonucleotides were nontoxic, lipid-permeable, high-affinity oligonucleotides. The miR-130/301 shortmer carried a sequence complementary to the active site of the miR-130/301 miRNA family, containing a phosphorothioate backbone and modifications (fluoro-, methoxyethyl, and bicyclic sugar) at the sugar 2’ position. Three days after the last injection, right heart catheterization was performed followed by harvesting of lung tissue for RNA extraction. Lung mRNA profiles of those mice or control mice (Normoxia+SU5416) were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000. The sequence reads that passed quality filters were analyzed at the gene-level count. The gene level counts were then normalized with the R/Bioconductor package limma using the voom /variance stabilization method. The data were quality controlled for outliers using principal component analysis (PCA). Differential expression analysis between transcriptome profiles of experimental groups was performed using the R / Bioconductor package limma. Results: Transcriptomic analyses of whole lung from mice with hypoxia+SU5416-induced PH revealed a generalized de-repression of miR-130/301 targets by Short-130 treatment. Importantly, although whole lung transcriptomics likely captured only a subset of the miR-130/301 targets affecting the diseased pulmonary vasculature, pathway enrichment nonetheless revealed pronounced representation of several pathways known to be involved in fibrosis. Thus, the miR-130/301 family indeed induces a programmatic shift at the molecular level toward the fibrotic pathophenotype in vivo
2015-09-29 | GSE61828 | GEO
Project description:Hypoxia is used as a model for pulmonary arterial hypertension. MiR-145 is upregulated in pulmonary arterial hypertension in humans and female mice. It has been observed that miR-145 knock out mice have reduced vascular remodelling in response to hypoxia. Therefore, knock down of miR-145 could be used as a therapy for pulmonary arterial hypertension in humans. This microarray has helped us to elucidate some of the pathways in the miR-145 knock out mice that may protect against vascular remodelling. Wild type (WT) mice and homozygous miR-145 -/- female mice (strain C57BL6J/129SVEV) at 8 weeks old were exposed to chronic hypoxia for 2 weeks or maintained in normoxic conditions and pulmonary arteries were dissected at 10 weeks of age. This study contained 4 groups, WT hypoxic, WT normoxic, miR-145 -/-, hypoxic miR-145 -/- normoxic each containing 6 animals. All adjacent comparisons were made to ananlyse the data (a 2 by 2 design).
2012-05-15 | E-MTAB-885 | biostudies-arrayexpress
Project description:Pulmonary hypertension (PH) and cancer pathophysiology share common signal transduction pathways leading to abnormal endothelial and smooth muscle cell interactions and angioproliferative vasculopathy. Sorafenib (Sor) a drug in clinical trials for cancer treatment, is an inhibitor of multiple kinases important in angiogenesis (Raf-1 kinase, VEGFR-2, VEGFR-3, PDGFR-ï¢)ï©. In this study, we assessed the efficacy of Sor as a potential therapy for PH, and hypothesized that Sor prevents the development of both a conventional and an augmented rodent model of PH. We performed studies in Dahl Salt-Sensitive rats (SS) exposed to hypoxia alone and in combination with the VEGFR-2 inhibitor, SU5416, known to induce a well-characterized augmented PH phenotype. Rats were, thus, divided into 5 groups: normoxia/vehicle (Norm), hypoxia/vehicle (H), hypoxia/ SU5416 (H-SU), hypoxia/Sorafenib (H-Sor) and hypoxia/ SU5416/ Sorafenib (H-SU-Sor). Except for the Norm group, all rats were maintained in a hypoxia chamber with a FiO2 of 10%. Rats received a single injection of SU5416 on Day 1 (20 mg/kg) and Sor solution was administered daily by gavage (2.5mg/kg). After 3.5 weeks, all rats were assessed by open chest catheterizations for pulmonary vascular and right ventricular pressures. Lung and heart tissue were harvested for histological and microarray analyses. Our results showed H-SU rats developed severe PH with changes in hemodynamic and histologic parameters when compared to Norm controls while rats exposed to H alone only displayed mildly elevated pressures compared with Norm. There was no significant change in pressures in the H-Sor or H-SU-Sor compared to Norm. Histopathology demonstrated a dramatic prevention of the PH phenotype in the H-SU-Sor rats with no significant remodeling compared with H-SU rats. Expression profiling data from H (n=4) and H-SU (n=3) rat lungs were compared to Norm (n=4) using normalization in R and SAM (δ>.639,) (minimum fold change >1.4). With false discovery rates (FDR) of 6.5% in hypoxia and 1.6% in H-SU, 1019 and 465 genes, respectively, were differentially-regulated compared to Norm. In addition, 38 genes were differentially expressed between H-SU and H-SU-Sor (n=4, FDR 6.7%) revealing a molecular signature with potentially novel target genes of Sor. Five differentially expressed genes (Tgfï¢3, C1qg, Nexn, Frzb, and Plaur) were examined by real-time RT-PCR and three were further validated by immunohistochemistry confirming the regulation on protein level. Based on the known pathways of hypoxic-induced PH and Sor, we further utilized immunohistochemistry to show the up-regulation of mediators of the MAPK cascade in the H and H-SU models of PH with subsequent, down-regulation by Sor. We therefore present Sor as a novel treatment for the development of severe PH and theorize that the MAPK cascade is a canonical pathway involved both in the development of PH and in the attenuation by Sor. This SuperSeries is composed of the following subset Series:; GSE8078: A Multi- Kinase Inhibitor Modulates Pulmonary Hypertension in a Rodent Model 1; GSE8132: A Multi- Kinase Inhibitor Modulates Pulmonary Hypertension in a Rodent Model 2 Experiment Overall Design: Refer to individual Series
2008-06-16 | E-GEOD-8134 | biostudies-arrayexpress
Project description:Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH is caused, among other factors, by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMC) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVEC). Upon re-exposure to normoxia, chronic hypoxia-induced PH in mice is reversible. In this study, we aim to identify novel candidate genes involved in pulmonary vascular remodeling specifically in the pulmonary vasculature.
2022-09-01 | GSE183908 | GEO
Project description:There is marked sexual dimorphism displayed in the onset and progression of pulmonary hypertension (PH). Females more commonly develop pulmonary arterial hypertension (PAH), however, females with PAH and other types of PH have better survival than males. Pulmonary microvascular endothelial cells play a crucial role in the pulmonary vascular remodelling and increased pulmonary vascular resistance of PH. Given this background, we hypothesized that there are sex differences in the pulmonary microvascular endothelium basally and in response to hypoxia that are independent of the sex hormone environment.
2024-01-03 | PXD046787 | Pride
Project description:Pulmonary hypertension (PH) is an incurable right heart failure disease. Parathyroid hormone (PTH) is secreted from the parathyroid gland and plays a crucial role in calcium homeostasis. PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We assessed whether the regulation of PTH affected PH in a hypoxia (Hx)-induced PH mouse model. PTH treatment exacerbated right ventricular hypertrophy and right ventricular systolic pressure in Hx mice. Our data showed how is PTH effected for PH model murine lung.
2023-10-11 | GSE244861 | GEO
Project description:This study is designed to investigate the protective function of cholinesterase inhibitor Donepezil (DON) in regulating Group III pulmonary hypertension (PH).
2023-02-16 | GSE211224 | GEO
Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. The levels of senescence marker, p16INK4A and senescence-associated β-galactosidase (SA-β-gal) activity are higher in PA endothelial cells (ECs) isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16fl/fl-Cdh5(PAC)-CreERT2 (p16iΔEC) mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing platelet-derived growth factor (PDGFB) expression. Transcriptomic analyses of IPAH patient or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and their interaction with TWIST1. Knockdown of p16INK4A attenuates the expression of PDGFB and TWIST1 in IPAH patient PAECs or hypoxia-treated mouse lungs and suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel implanted on the mouse lungs. Hypoxia-treated mouse lung EC-derived exosomes stimulate DNA synthesis and migration of PASMCs in vitro and in the gel implanted on the mouse lungs, while p16iΔEC mouse lung EC-derived exosomes inhibit the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.
2022-10-15 | PXD033549 | Pride
Project description:SRY-Box Transcription Factor 17 (SOX17) enhancers variants and mutations are found in patients with pulmonary arterial hypertension (PAH). In human PAH pulmonary microvascular endothelial cells (HPMVEC), there is a significant downregulation of SOX17 expression. We hypothesized that SOX17 deficiency contributes to the pathogenesis of PAH and found that mice with endothelial specific disruption (ecKO Sox17) developed spontaneous pulmonary hypertension (PH) and exacerbated hypoxia-induced PH. Loss of SOX17 in lung ECs induces cell cycle programming, proliferative and anti-apoptotic phenotypes, a process mediated by the activation of E2F Transcription Factor 1 (E2F1) signaling. Pharmacological inhibition of E2F1 in ecKO Sox17 mice attenuated PH and cell cycle programming. Our study demonstrated that endothelial SOX17 deficiency induces PH and targeting E2F1 signaling represents a promising approach in PAH patients.
2023-03-15 | GSE192649 | GEO
Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the non-muscularized distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. Here, we have demonstrated that endothelial senescence mediates PH pathology by increasing platelet-derived growth factor (PDGFB) expression. The levels of senescence markers p16INK4A and senescence-associated β-galactosidase (SA-β-gal) are higher in PA endothelial cells (ECs) isolated from IPAH patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16INK4Afl/fl-Cdh5(PAC)-CreERT2 mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing PDGFB expression. Transcriptomic analyses of idiopathic pulmonary arterial hypertension (IPAH) patient lung ECs or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and interaction with TWIST1. Increases in the levels of PDGFB and TWIST1 in hypoxia-treated mouse lung ECs or IPAH patient lung ECs are attenuated by knocking down p16INK4A expression or treating with senolytic reagents. Knockdown of p16INK4A also suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel. Exosomes collected from hypoxia-treated mouse lung ECs stimulate SMC DNA synthesis and migration in vitro and in the gel implanted on the mouse lungs, while p16INK4A knockdown in ECs inhibits the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.
2022-10-12 | GSE193272 | GEO