Dataset Information

Novel Targets in a High-Altitude Pulmonary Hypertension Rat Model Based on RNA-seq and Proteomics.

ABSTRACT: High-altitude pulmonary hypertension (HAPH) is a complication arising from an inability to acclimatize to high altitude and is associated with high morbidity and mortality. We aimed to analyze the effects of macitentan, selexipag, riociguat, and reoxygenation on HAPH, and to screen possible targets of these treatments for future drug screening. Rats were subjected to hypobaric hypoxia for 35 days to induce HAPH, and treated with vehicle or selexipag, macitentan, riociguat, or with reoxygenation, from days 21 to 35. Selexipag, macitentan, and reoxygenation prevented an increase in mean pulmonary artery pressure and hypoxia-induced right ventricular hypertrophy, compared to the vehicle. Riociguat had little effect. RNA-seq and proteomics revealed strong correlations between responses to the three drugs, which had almost identical effects. GO-enrichment revealed that the differentially expressed genes included those involved in metabolic regulation, transcription, and translation. Various molecular pathways were annotated. Selexipag, macitentan, and reoxygenation ameliorated HAPH. Serpina1, Cryz, and Cmc1 were identified, via multi-omics screening, as key genes involved in HAPH. These findings provide new insights into the targeted drug mechanisms in HAPH.

SUBMITTER: Xu X

PROVIDER: S-EPMC8595261 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Novel Targets in a High-Altitude Pulmonary Hypertension Rat Model Based on RNA-seq and Proteomics.

Xu Xiang X Li Hanlu H Wei Qingxia Q Li Xin X Shen Yanying Y Guo Ge G Chen Yibing Y He Kunlun K Liu Chunlei C

Frontiers in medicine 20211103

High-altitude pulmonary hypertension (HAPH) is a complication arising from an inability to acclimatize to high altitude and is associated with high morbidity and mortality. We aimed to analyze the effects of macitentan, selexipag, riociguat, and reoxygenation on HAPH, and to screen possible targets of these treatments for future drug screening. Rats were subjected to hypobaric hypoxia for 35 days to induce HAPH, and treated with vehicle or selexipag, macitentan, riociguat, or with reoxygenation, ...[more]

PMID: 34805208

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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 (Î´>.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. Experiment Overall Design: Rats were divided into 5 groups of which 4 groups were analyzed by microarrays: normoxia/vehicle (n=4), hypoxia/vehicle (n=4), hypoxia/ SU5416 (n=3), and hypoxia/ SU5416/ Sorafenib (n=4). RNA was harvested from lung tissue at 3.5 weeks.Expression profiling data from H and H-SU rat lungs were compared to Norm using normalization in R and SAM (Î´>.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 (FDR 6.7%) revealing a molecular signature with potentially novel target genes of Sor.

Dataset Information

Novel Targets in a High-Altitude Pulmonary Hypertension Rat Model Based on RNA-seq and Proteomics.

Publications

Novel Targets in a High-Altitude Pulmonary Hypertension Rat Model Based on RNA-seq and Proteomics.

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