Single-cell transcriptomics reveal diverging pathobiology and opportunities for precision targeting in scleroderma -associated versus idiopathic PAH
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PROVIDER: PRJNA1245292 | ENA |
REPOSITORIES: ENA
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Project description:Pulmonary arterial hypertension (PAH) is characterized by progressive cellular and molecular changes within the pulmonary vasculature that lead to structural remodeling, rising pulmonary vascular resistance and, if untreated, right ventricular failure. In clinical practice, PAH treatments have evolved little over the last two decades, and until recently, all approved therapies have targeted one of three molecular pathways: the nitric oxide (NO) signaling pathway, the endothelin pathway, or the prostacyclin pathway. With these therapies, treatment responses have been modest and variable, with patients experiencing a heterogeneity of treatment effects. In particular, patients with PAH related to systemic sclerosis (SSc-PAH) have derived less benefit from PAH-specific therapies and have experienced worse clinical outcomes compared to other PAH subgroups. We and others have shown that in SSc-PAH, pathophysiologic differences at the molecular, cellular, and tissue levels underlie observed differences in clinical outcomes. A detailed understanding of the molecular aberration present in SSc-PAH versus idiopathic PAH (IPAH) might allow for exploitation of aberrant signaling pathways that are unique to SSc-PAH (and/or present in both of these two common PAH subtypes) for drug targeting. Recently, the approval of sotatercept, a novel ligand-trap molecule that targets TGF-beta signaling in PAH, was based on randomized controlled trial data demonstrating clinical improvement in patients already treated with drugs targeting NO, endothelin, and/or prostacyclin signaling. The success of sotatercept therefore lends credence to the notion that targeting as-yet unaddressed molecular aberrancies can bring about additional clinical benefit. Most previous omics investigations in PAH have examined circulating plasma or serum. With this study, we sought to identify distinct and overlapping gene expression patterns in SSc-PAH versus IPAH human lung tissue as a means of implicating abnormal biological processes, including inferred gene regulation and cell signaling, unique to the organ manifesting disease. To maximize biologic insight, we took a single-cell approach to RNA sequencing, in contrast to the bulk sequencing performed in most previous PAH studies. Finally, we leveraged cell-specific gene expression patterns and established computational methods to identify small molecule compounds with high potential to reverse disease-specific expression signatures, as a means of prioritizing candidates for drug repositioning. We posit that generation of phenotype-specific high-dimensional omics datasets, such as this one, will enable a precision-targeted approach to molecular aberration that might improve therapeutic responses and resolve heterogeneous treatment effects, thereby improving clinical outcomes across PAH subtypes.
2025-06-06 | GSE293580 | GEO
Project description:IntroductionPulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide (NO), endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH).MethodsLung tissue samples from four SSc-PAH, four IPAH, and four failed donor specimens were obtained from the Pulmonary Hypertension Breakthrough Initiative (PHBI) lung tissue bank. Single-cell RNA sequencing (scRNAseq) was performed using the 10X Genomics Chromium Flex platform. Data normalization, clustering, and differential expression analysis were conducted using Seurat. Additional analyses included gene set enrichment analysis (GSEA), transcription factor activity analysis, and ligand-receptor signaling. Pharmacotranscriptomic screening was performed using the Connectivity Map.ResultsSSc-PAH samples showed a higher proportion of fibroblasts and dendritic cells/macrophages compared to IPAH and donor samples. GSEA revealed enriched pathways related to epithelial-to-mesenchymal transition (EMT), apoptosis, and vascular remodeling in SSc-PAH samples. There was pronounced differential gene expression across diverse pulmonary vascular cell types and in various epithelial cell types in both IPAH and SSc-PAH, with epithelial to endothelial cell signaling observed. Macrophage to endothelial cell signaling was particularly pronounced in SSc-PAH. Pharmacotranscriptomic screening identified TIE2, GSK-3, and PKC inhibitors, among other compounds, as potential drug candidates for reversing SSc-PAH gene expression signatures.DiscussionOverlapping and distinct gene expression patterns exist in SSc-PAH versus IPAH, with significant molecular differences suggesting unique pathogenic mechanisms in SSc-PAH. These findings highlight the potential for precision-targeted therapies to improve SSc-PAH patient outcomes. Future studies should validate these targets clinically and explore their therapeutic efficacy.
| S-EPMC11527343 | biostudies-literature
Project description:To identify dysregulated miRNAs in PAH HPASMC, we compared the miRNA expression profiles between normal and PAH HPASMC using the RT2 miRNA PCR Array System. Total RNA was isolated using a miRNeasy Mini Kit (Qiagen, Valencia, CA) and treated with an RNase-Free DNase Set (Qiagen). After quantification with Nanodrop 2000 spectrophotometer (ThermoScientific, Rockford, IL), miRNAs were reversely transcribed using a RT2 miRNA First Strand Kit (SABiosciences, Frederick, MD). The RT2 miRNA PCR Array System (SABiosciences) was used to study miRNA profiling in normal and PAH HPASMC. U6, SNORD44, SNORD47 and SNORD48 were used as internal controls for the profiling. HPASMC isolated from oe normal donor (C128, as control), one IPAH patient (B157), one PAH patient with Eisenmenger’s syndrome (CC-008) and one PAH patient with Scleroderma (CCF-004) were used for miRNA PCR array study. Data is normalized to the control sample. Three independent sample preparations were used for this study.
2014-02-28 | E-GEOD-55427 | biostudies-arrayexpress
Project description:This experiment was performed using the following cohorts: 1) healthy controls, 2) patients with scleroderma at low risk for pulmonary hypertension, 3) pateints with scleroderma at high risk for pulmonary hypertension who underwent a catheterization and were found to have normal pressures, borderline elevated pressures or pulmonary arterial hypertensino (PAH). Whole blood was drawn directly into EDTA tubes at rest and again at peak exercise for each human subject. The samples were processed to plasma by MCRU and stored at -80 in the Biorepository.
2018-08-02 | MSV000082744 | GNPS
Project description:The study looked at changes in gene expression profiles in subjects with Pulmonary Arterial Hypertension and Scleroderma (PAH-SSc) before and after treatment with Tadalafil. A total of ten subjects were enrolled and various clinical assessments including 6-minute walk tes, cardiac MRI and right heart catheterization were done in addition to gene expression study.
2016-08-26 | GSE75173 | GEO
Project description:Pregnancy-associated hypertensive (PAH) mice were maintained by mating females carrying the human angiotensinogen (hAGT) gene with males expressing the human renin (hRN) gene, as previously described (Takimoto E., et al., Science, 1996). Angiotensin II (AngII) has critical roles in regulation of blood pressure. In late pregnancy of PAH mice, increased AngII causes acute and severe hypertension with proteinuria. Furthermore, PAH mice show cardiac hypertrophy, fibrosis and apoptosis. It is known that AngII downregulates mRNA of alpha 1a-adrenergic receptor (Adra1a) in neonatal rat cardiac myocytes (Li H.T., et al., Circ. Res., 1997). Interestingly, we found that Adra1a knock out PAH (PAH/aKO) mice display more severe phenotype of cardiac hypertrophy in comparison to PAH mice. In this study, to understand the molecular basis of cardiac hypertrophy via regulation of Adra1a expression with AngII in PAH mice, we performed a comprehensive analysis of gene expression changes in cardiac remodeling of PAH and PAH/aKO mice using the next-generation RNA sequencing (RNA-seq).
2023-01-27 | GSE140948 | GEO
Project description:PAH was induced by 60mg/kg MCT and an aorto-caval shunt. At different timepoints of PAH progression (day 14, 21 and 28 after MCT-injection), the left lung with PAH was hemodynamically unloading by unilateral orthotopic transplatation into a syngeneic, healthy recipient. All day 14 and 7/10 day 21 transplanted lungs showed reversal of PAH after LTx. All day 28 and 3/10 day 21 transplanted lungs showed PAH progression after LTx. Lung tissue of Reversible and Irreversible PAH and normal controls, acquired at LTx, was compared using RNA-seq.
2020-07-01 | GSE149899 | GEO