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Genomic alterations during the progress of pulmonary hypertension

ABSTRACT: Pulmonary hypertension (PH), a rare disorder is a complication of a number of cardiopulmonary, unrelated systemic diseases, drug toxicity and genetic mutations. Major advances have been made in the field, but the pathogenesis of PH is not yet understood. Several experimental models such as monocrotaline (MCT) and hypoxia have been used to understand the mechanism underlying the pathogenesis of PH. We have recently shown that that the addition of hypoxia to MCT injected rats accelerates the disease process leading to neointima formation. We have profiled the lungs of adult male Sprague-Dawley rats kept for 4 weeks in normal atmospheric conditions or in hypobaric hypoxia (380 mmHg) w/o subcutaneous injection with 40 mg/kg MCT or just saline. While MCT and hypoxia altered expression of few genes when applied separately, together they induced a substantial alteration of the transcriptome. The most profoundly altered pathways by the combined effect of hypoxia and MCT were: endocytosis, apoptosis, HIF-1 signaling pathway and vascular smooth muscle contraction.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE72707 | GEO | 2015/09/04

SECONDARY ACCESSION(S): PRJNA294702

REPOSITORIES: GEO

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Genomic alterations during the progress of pulmonary hypertension

Project description:Pulmonary hypertension (PH), a rare disorder is a complication of a number of cardiopulmonary, unrelated systemic diseases, drug toxicity and genetic mutations. Major advances have been made in the field, but the pathogenesis of PH is not yet understood. Several experimental models such as monocrotaline (MCT) and hypoxia have been used to understand the mechanism underlying the pathogenesis of PH. We have recently shown that that the addition of hypoxia to MCT injected rats accelerates the disease process leading to neointima formation. We have profiled the lungs of adult male Sprague-Dawley rats kept for 4 weeks in normal atmospheric conditions or in hypobaric hypoxia (380 mmHg) w/o subcutaneous injection with 40 mg/kg MCT or just saline. While MCT and hypoxia altered expression of few genes when applied separately, together they induced a substantial alteration of the transcriptome. The most profoundly altered pathways by the combined effect of hypoxia and MCT were: endocytosis, apoptosis, HIF-1 signaling pathway and vascular smooth muscle contraction. Two-condition (C = normal atmospheric conditions (control) vs H = hypobaric hypoxia) + two treatment (M = with MCT, O = without MCT) experiment. Four biological replicas of each combination: CO, HO, CM, HM. Differently labeled biological replicates were cohybridized with each array. Results of similarly labeled different conditions were compared then averaged for the two fluorescent labels. For instance: CO1 & CO3 were compared with CM1 & CM3, CO2 & CO4 were compared with CM2 & + CM4, and the results of the comparisons averaged. This design uses 100% of the resources, has a better normlaiztion and allows all possible comparisons among the conditions.

2015-09-04 | E-GEOD-72707 | biostudies-arrayexpress

PDZ-Binding Kinase, a Novel Regulator of Vascular Remodeling in Pulmonary Arterial Hypertension

2024-01-11 | GSE252564 | GEO

Compensated and decompensated hypertrophy after monocrotaline injection

Project description:14 days after a single subcutaneous monocrotaline (MCT) injection we isolated the left and right ventricles from wistar rats. Factor1: Comparison between control (CON), compensated hypertrophy (HYP), and decompensated hypertrophy (CHF). Factor2: Comparison between left ventricle (LV) and right ventricle (RV). Keywords: dose response

2004-08-18 | GSE1652 | GEO

Transcriptome profiling based study of early gene responses in susceptible and tolerant rat lung tissues during acute hypobaric hypoxia

Project description:Aim: Acute hypobaric hypoxia occurs during fast ascent and brief sojourns to high altitudes. We aimed to elucidate early phase molecular mechanisms during hypobaric hypoxia that may contribute towards differential physiological responses in susceptible and tolerant rats. Methods: Sprague-Dawley rats representing susceptible, normal (moderate) and tolerant male and female groups were subjected to simulated acute hypobaric hypoxia for one hour at 9144 m and 24°C. The lung tissue samples were subjected to high throughput mRNA-seq based transcriptome profiling. Differential gene expression of selected genes was validated by qRT-PCR. Results: The cellular mechanisms found to be playing significant role in hypobaric hypoxia included MAPK, p53 and JAK-STAT signaling, and hypometabolism. Upregulated expression of early response genes including Dusp1, Cdkn1a, Txnip, Rgs1 and Rgs2 in susceptible rats indicated a progression towards growth arrest and apoptosis, while elevated expression of cell adhesion molecules, wound healing and repair bioprocesses was found in tolerant males. Upregulated Kcnj15 and Vsig4 variants in tolerant females suggested hypoxia adaptation by fluid reabsorption to avoid edematous conditions and suppression of T cell proliferation to avoid acute lung inflammation. Conclusion: The differential gene expression patterns in different experimental sets elucidated the physiological mechanisms associated with progressive damage in the lung tissues of susceptible and normal (moderate) rats, and tissue protective measures in tolerant rats during acute hypobaric hypoxia.

2018-07-01 | GSE62688 | GEO

Nitrated protein profile of rat hypoxic brain

Project description:In this work we have described the protein nitration profile in the brain of rats submitted to an experimental model of hypobaric hypoxia

2014-07-30 | PXD001049 | Pride

The expression signatures of circRNA in MCT-induced pulmonary arterial hypertension rat

Project description:To investigate the underlying mechanism of pulmonary hypertension, the model of monocrotaline (MCT)-treated pulmonary arterial hypertension (PAH) rats were constructed to detect the differentially expressed profile of circRNAs in lung tissue of PAH rat. The whole genome microarray expression profiling analysis as a discovery platform have been employed to identify genes difference.

2023-09-12 | GSE227339 | GEO

Quantitative proteomic and phosphoproteomic profiling of lung and heart tissues from Pulmonary arterial hypertension model rats

Project description:TMT-based quantitative proteomics was performed on lung tissues derived from SD rats which were treated with monocrotaline （MCT） for 1to 4 weeks. Similar analysis was performed with RV tissues from rats treated with MCT for 3 weeks. In addition, phosphoproteomic analysis was performed with lung and RV from rats treated with MCT for 3 weeks.

2022-11-25 | PXD038462 | iProX

LncRNA expression profile and their possible regulatory role in the HSOS induced by monocrotaline in rats

Project description:Aims: Long noncoding RNA (lncRNAs) contribute in regulating vital physiological processes and pathogenesis of many diseases. Monocrotaline can cause large-scale outbreaks of toxic liver disease in humans and animals as hepatic sinusoidal obstruction syndrome (HSOS). This research aimed to study the lncRNA-mRNA regulation network in MCT-induced HSOS in rats. Main methods: We established MCT-induced HSOS, and then carried out microarray to liver tissues of SD rat of an early HSOS model (MCT-12h treated and control groups) to investigate the differentially expressed lncRNAs and mRNAs in the early hepatotoxicity, followed by RT-PCR for selected lncRNAs, which were markedly changed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome analysis were also conducted Key findings. According to analysis, LncRNAs might play an essential role in the hepatotoxicity mechanism. Significance: This study provides a basis for further researches on the molecular mechanisms, and treatment of MCT-induced hepatotoxicity, especially in the early stage, which is pivotal to treat it successfully before irreversible liver damage occur.

2023-03-02 | GSE213031 | GEO

RNA sequencing analysis of monocrotaline-induced pulmonary arterial hypertension

Project description:Inflammation and immunity play a causal role in the pathogenesis of pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). However, the pathways and mechanisms by which inflammation and immunity contribute to pulmonary vascular remodeling remain unknown. RNA sequencing was used to analyze the transcriptome in control and rats injected with monocrotaline (MCT) for 1, 2, 3 and 4 weeks. Using the transcriptional profiling of MCT-induced PAH coupled with bioinformatics analysis, we clustered the differentially expressed genes (DEGs) and chose the increased expression patterns associated with inflammatory and immune response. We found the enrichment of Toll-like receptor (TLR) and NOD-like receptor (NLR) pathways and identified NF-κB-mediated inflammatory and immune profiling in MCT-induced PAH. Pathway-based data integration and visualization showed the dysregulated TLR and NLR pathways, including increased expression of TLR2 and NLRP3, and their downstream molecules. Further analysis revealed that the activation of TLR and NLR pathways was associated with upregulation of damage-associated molecular patterns (DAMPs) and RIPK3-mediated necroptosis was involved in the generation of DAMPs in MCT-induced PAH. Collectively, we identify RIPK3-mediated necroptosis and its triggered TLR and NLR pathways in the progression of pulmonary vascular remodeling, thus, providing novel insights into the mechanisms underlying inflammation and immunity in the pathogenesis of PAH.

2020-05-02 | GSE149713 | GEO

IL-6/gp130 signaling in CD4+ T cells drives the pathogenesis of pulmonary hypertension

Project description:Pulmonary arterial hypertension (PAH) is characterized by stenosis and occlusions of small pulmonary arteries, leading to elevated pulmonary arterial pressure and right heart failure. Although accumulating evidence shows the importance of interleukin (IL)-6 in the pathogenesis of PAH, the target cells of IL-6 are poorly understood. Using mice harboring the floxed allele of gp130, a subunit of IL-6 receptor, we found substantial Cre recombination in all hematopoietic cell lineages from the primitive hematopoietic stem cell level in SM22α-Cre mice. We also revealed that a CD4+ cell-specific gp130 deletion ameliorated the phenotype of hypoxia-induced pulmonary hypertension in mice. Disruption of IL-6 signaling via deletion of gp130 in CD4+ T cells inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and suppressed the hypoxia-induced increase in T helper 17 cells. To further examine the role of IL-6/gp130 signaling in more severe PH models, we developed Il6 knockout (KO) rats using the CRISPR/Cas9 system and showed that IL-6 deficiency could improve the pathophysiology in hypoxia-, monocrotaline-, and Sugen5416/hypoxia (SuHx)-induced rat PH models. Phosphorylation of STAT3 in CD4+ cells was also observed around the vascular lesions in the lungs of SuHx rat model, but not in Il6 KO rats. Blockade of IL-6 signaling had an additive effect on conventional PAH therapeutics, such as endothelin receptor antagonist (macitentan) and soluble guanylyl cyclase stimulator (BAY41-2272). These findings suggest that IL-6/gp130 signaling in CD4+ cells plays a critical role in the pathogenesis of PAH.

2024-04-12 | GSE255994 | GEO

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