RARE DISEASE
Idiopathic pulmonary arterial hypertension
Idiopathic pulmonary arterial hypertension
Idiopathic pulmonary arterial hypertension
Synonyms: IPAH, Primary pulmonary arterial hypertension
Synonyms: IPAH, Primary pulmonary arterial hypertension
Synonyms: IPAH, Primary pulmonary arterial hypertension
Drug discovery
9
drugs
With orphan designations
Overview
Idiopathic pulmonary arterial hypertension (IPAH) is a rare, progressive disease of small pulmonary arteries characterized by vascular remodeling, elevated pulmonary vascular resistance (>2 Wood units), and mean pulmonary arterial pressure >20 mmHg [1][6]. It leads to right ventricular failure and premature death, with nonspecific presenting symptoms like exertional dyspnea, fatigue, and syncope [1][4][6]. Diagnosis requires exclusion of secondary causes [1][6]. Treatment combines vasodilators, antiproliferative agents, and advanced interventions [3][8][13], though prognosis remains guarded without transplantation [10][16].
Categories: rare genetic diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
3,563 drug discovery papers about Idiopathic pulmonary arterial hypertension, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,563 drug discovery papers about Idiopathic pulmonary arterial hypertension, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Effect of supplemental oxygen therapy on 6-min walk distance in patients with pulmonary arterial hypertension living at 2850 m: a randomised, crossover trial.
Patients with pulmonary arterial hypertension (PAH) who permanently live at high altitude (>2500 m) face particular challenges due to hypobaric hypoxia, which may exacerbate pulmonary hypertension and impair exercise capacity. We therefore investigated the effect of low-dose supplemental oxygen therapy (SOT) on 6-min walk distance (6MWD) in high-altitude residents diagnosed with PAH. Adults diagnosed with PAH who permanently live at >2500 m performed two 6MWD tests, once with SOT (1-2 L·min-1 via nasal cannula provided by a portable back-packed concentrator) and once while breathing ambient air (air) at 2850 m according to a randomised, controlled, crossover trial. The primary outcome was the difference in 6MWD between SOT and air. Secondary outcomes were effects of SOT on heart rate, blood pressure and peripheral oxygen saturation (S pO2 ) and Borg scale. 28 patients (86% women, mean±sd age 45±12 years, resting S pO2 93±3%, mean pulmonary artery pressure 52±16 mmHg, 6MWD at 2850 m 462±100 m) were included. SOT compared to hypoxic air at 2850 m did not improve 6MWD (mean difference -5 m, 95% CI: -24 to 14 m, p=0.576), dyspnoea, leg discomfort or end-exercise S pO2 , but did increase resting S pO2 . In high-altitude residents diagnosed with PAH, low-dose SOT as commonly prescribed via portable concentrator did not improve 6MWD nor dyspnoea perception, most likely due to insufficient flow provided by the concentrator during exercise, further lowered by exertional mouth breathing and the weight of the backpacked concentrator.
2026-09-24 | Long-Term Survival in Pulmonary Arterial Hypertension with Different Etiologies: A Single-Center Experience.
Pulmonary arterial hypertension (PAH) is a progressive disease with variable etiologies and poor prognosis. Long-term outcome data across etiologies remain limited. We retrospectively studied 70 patients with PAH confirmed by right heart catheterization at Kaohsiung Chang Gung Memorial Hospital (2005-2023). Baseline characteristics, World Health Organization (WHO) functional class (FC), 6-minute walk distance, hemodynamics, comorbidities, and treatment regimens were collected. Survival was analyzed using the Kaplan-Meier method. The mean age of the patients was 55 years, and 59% were female. Connective tissue disease (CTD) was the leading etiology (35.7%), followed by idiopathic PAH (24.3%) and congenital heart disease (21.4%). The overall survival rates were 80.9%, 76.6%, and 73.4% at 1, 3, and 5 years, respectively. WHO FC IV at diagnosis was significantly associated with worse survival (p < 0.05). Although patients with CTD-PAH had a numerically lower survival rate compared to other etiologies, the difference did not reach statistical significance. Chronic kidney disease (CKD) and coronary artery disease (CAD) were associated with increased mortality. Combination therapy was associated with numerically higher survival (91.8%, 87.0% and 80.8% at 1, 3 and 5 years, respectively) compared to monotherapy or no therapy, although without statistical significance. Baseline risk stratification using the COMPERA 2.0 four-strata model was significantly associated with survival (p < 0.05). CTD etiology, advanced FC, and comorbid CKD or CAD were associated with a poor prognosis in our cohort of patients with PAH. Combination therapy may improve long-term outcomes.
2026-09-23 | Pulmonary arterial hypertension with signs of venous/capillary involvement in connective tissue diseases: paradigms and paradoxes.
Pulmonary arterial hypertension (PAH) with features of venous and/or capillary involvement, formerly pulmonary veno-occlusive disease (PVOD), represents a rare and severe subset of pulmonary hypertension. While PVOD is typically idiopathic, heritable or drug/toxin-induced, "PVOD-like" features have long been recognised in PAH associated with connective tissue diseases (CTDs), especially systemic sclerosis (SSc). This review synthesises the available evidence on this phenotype, integrating published data with an unreported cohort of 25 patients. Venular remodelling is a frequent histological finding in SSc-PAH lung explants, but high-resolution computed tomography (HRCT) signs of PVOD are inconsistently observed at PAH presentation, reflecting a progression of the lung vasculopathy and/or an unmasking effect of pulmonary vasodilators. Patients often exhibit major functional limitation, profound impairment in gas transfer and severe haemodynamic compromise. Assessing venular involvement in SSc-PAH poses unique challenges, due to possible lung fibrosis on HRCT and differential diagnosis with an occult post-capillary component. Despite the lack of robust evidence, PAH-approved therapies are commonly used, although with caution due to a high risk of pulmonary oedema with pulmonary vasodilators. As these patients also display significant arteriolar involvement, which can benefit from these drugs, dedicated treatment strategies warrant further investigation. Prognosis remains dismal, with a 5-year survival around 45-50%. Similar PVOD-like patterns have also anecdotally been reported in systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, Sjögren syndrome and inflammatory myopathies, with comparable features. Overall, PVOD-like disease in CTD-PAH constitutes a high-risk phenotype with unresolved pathogenic and management challenges, requiring refined patient stratification and improved therapeutic strategies.
2026-09-23 | Iron and the lung: emerging roles of iron metabolism in pulmonary disease pathogenesis and therapy.
Iron is an essential micronutrient, but its redox reactivity also renders it potentially toxic. The lungs are particularly vulnerable to iron-dependent oxidative injury due to continuous exposure to high oxygen tension, environmental particles, and microbial pathogens. Pulmonary iron homeostasis is therefore tightly regulated at systemic, cellular, and local levels through coordinated actions of transferrin, ferritin, ferroportin, hepcidin, and the iron responsive element/iron regulatory protein system. Disruption of these pathways contributes to a broad spectrum of pulmonary diseases. In COPD, asthma, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, infectious lung diseases, and lung cancer, iron dysregulation promotes oxidative stress, ferroptosis, inflammation, aberrant repair, vascular remodelling, or pathogen persistence. Notably, systemic iron deficiency may coexist with local pulmonary iron overload, highlighting the compartmentalised nature of lung iron metabolism. Emerging experimental and clinical evidence suggests that therapeutic manipulation of iron availability through supplementation, chelation or targeting iron-dependent pathways may be beneficial in selected contexts. A deeper mechanistic understanding and improved biomarkers will be essential for developing disease-specific iron-modulating strategies.
2026-09-17 | Proteogenomic Profiling of Idiopathic Pulmonary Arterial Hypertension Identifies Sex-Differential Proteins and Candidate Therapeutic Targets.
Current biomarkers for idiopathic pulmonary arterial hypertension (IPAH) lack disease specificity and provide limited biological insight. We hypothesized that integrating population-based proteomics with genetic evidence would identify robust IPAH-associated proteins relevant to risk stratification, early detection, prognosis, sex differences, and candidate drug-repurposing opportunities. We analyzed 2,918 plasma proteins in 44,137 predominantly European-ancestry UK Biobank participants aged 40-69 years, including 252 incident and 141 prevalent IPAH cases. Proteins associated with IPAH were identified using Cox and logistic regression analyses, prioritized by cis-Mendelian randomization, and assessed through cross-ancestry effect-direction concordance and sensitivity analyses. Unsupervised clustering, nested cross-validated prediction models, and target-drug annotation were used for downstream evaluation. Eighteen proteins showed convergent epidemiological and genetic evidence, and 12 remained supported in cross-ancestry and sensitivity analyses. These proteins defined a high-mortality endotype characterized by vascular and ventricular remodeling. Combined clinical and proteomic models achieved AUCs of 0.779 for incident IPAH and 0.768 for mortality. Proteomic contributions differed by sex, and target-drug annotation identified six drug-linked proteins, highlighting ANXA2-linked Artenimol as a repurposing candidate. Twelve biologically plausible IPAH-associated proteins inform risk stratification, prediction, sex-related characterization, and therapeutic prioritization. Independent multi-ancestry validation and mechanistic studies are warranted.
cell therapies
2026-06-25 | Tracheal Delivery of HO-1-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cells Treats Pulmonary Arterial Hypertension by Enhancing Pulmonary Antioxidant and Anti-inflammatory Responses.
Pulmonary arterial hypertension (PAH) is a life-threatening cardiovascular disease, with current treatments only alleviating symptoms. Mesenchymal stem cells (MSCs) possess immune-regulatory and reparative properties, and HO-1-modified MSCs enhance their anti-inflammatory and antioxidant effects. This study aims to investigate the potential of tracheal delivery of HO-1-modified MSCs for the treatment of PAH. This study first assessed the levels of inflammation and oxidative stress in the lung tissue pathology of donors and IPAH patients, detecting F4/80, IL-6, and the oxidative stress marker 8-OHdG. Subsequently, in MCT-induced rat and hypoxia-exposed mouse models, we evaluated lung tissue sections for HE staining and α-SMA immunohistochemistry, along with antioxidant enzymes (SOD, CAT, GSH) and inflammatory factors (TNF-α, IL-18, IL-6, IL-1β) at 1, 2, 3, 4, and 5 weeks to assess the effects of various treatments. Next, we compared the anti-inflammatory and antioxidant capacities of HO-1-modified MSCs derived from umbilical cord (UC-MSCs) and adipose tissue (AD-MSCs), selecting the best cell intervention strategy. Using in vivo imaging, we assessed the cell homing of intravenously injected cells and drug retention after tracheal delivery. After tracheal delivery of HO-1-MSCs at 3, 4, and 5 weeks, we analyzed IHC staining for α-SMA, right heart catheterization, lung tissue inflammation, and antioxidant stress markers to identify the optimal intervention window. The efficacy was also compared with traditional HO-1 pharmacological agonists. Finally, the effects of HO-1-MSCs on vascular cells (PAECs, PASMCs) and immune cells (myeloid-derived/macrophage, myeloid-derived neutrophils) in vivo were further explored to evaluate their potential and mechanisms in PAH treatment. Compared to donor controls, IPAH patient lung tissues exhibited significant inflammation and oxidative stress, with increased macrophage infiltration and elevated levels of IL-6 and 8-OHdG. In MCT rat and hypoxia mouse models, PAH development was associated with vascular remodeling, persistent inflammation, and oxidative stress. UC-MSCs showed stronger anti-inflammatory and antioxidant effects than AD-MSCs. Tracheal delivery of HO-1-MSCs significantly improved outcomes at weeks 3 and 4, reversing pulmonary vascular remodeling, reducing pulmonary artery pressure, inhibiting IL-6 and IL-18 expression, and restoring antioxidant enzyme activity (SOD and CAT). Compared to traditional HO-1 agonists, HO-1-MSCs demonstrated superior efficacy. Additionally, HO-1-MSCs effectively inhibited PAEC proliferation, suppressed the activation of the ERK/AKT pathway, reduced smooth muscle cell proliferation and migration, significantly decreased neutrophil activation, and promoted M2 macrophage polarization while reducing the M1 macrophage population. Tracheal delivery of HO-1-(UC)-MSCs effectively alleviates inflammation and oxidative stress in PAH, improves vascular remodeling and pulmonary artery pressure, and offers a promising new therapeutic strategy for PAH treatment.
2026-03-09 | Pulmonary Artery Denervation for Refractory Sjögren's Syndrome-Associated Pulmonary Arterial Hypertension: A Case Report of Combined Hemodynamic and Renal Recovery.
A 31-year-old woman with primary Sjögren's syndrome presented with severe pre-capillary pulmonary arterial hypertension (mean pulmonary arterial pressure 51 mmHg, pulmonary vascular resistance 14.7 Wood units) and active renal impairment (24-hour urinary protein 1290 mg). Despite initial immunosuppressive therapy and dual oral PAH-targeted treatment with ambrisentan and tadalafil, she remained at high risk. She subsequently underwent pulmonary artery denervation (PADN) using a 45-mm ablation catheter with 120-second radiofrequency applications at three sites on the main pulmonary artery. At 2-month follow-up, she demonstrated significant symptomatic improvement to WHO functional class I, with a 6-minute walk distance of 320 meters, improved hemodynamics (mean pulmonary arterial pressure 35 mmHg, pulmonary vascular resistance 5.63 Wood units), and a reduced NT-proBNP level of 320 pg/mL, achieving an intermediate-low risk status according to the 2022 ESC/ERS guidelines. Renal function also improved (24-hour urinary protein 158 mg). This case suggests that PADN may be an effective adjunctive interventional strategy for refractory autoimmune PAH, even with concurrent renal involvement, facilitating simultaneous cardiopulmonary and renal recovery.
2026-01-15 | CD19 CAR T-cell therapy for connective tissue disease-associated pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs), including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), mixed connective tissue disease, and inflammatory myositis [1]. Patients with CTD-associated PAH exhibit significantly reduced long-term survival compared to those without PAH [2–6]. The refractory nature of underlying CTDs contributes to progressive clinical deterioration and poor outcomes. Current treatments beyond conventional immunosuppression and pulmonary vasodilators remain limited. Emerging evidence implicates B-cell dysregulation in PAH pathogenesis [7, 8]. CD19 chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in refractory CTDs, including SSc and SLE [9, 10]. Herein, we report the first successful application of CD19 CAR T-cell therapy in a patient with CTD-associated PAH.
2025-12-17 | Generation of 5 hiPSC lines from pediatric patients with Heritable pulmonary arterial hypertension (HPAH) caused by heterozygous mutations in the TBX4 gene.
Heritable pulmonary arterial hypertension (HPAH) and underlying pulmonary vascular disease (PVD) are often caused by TBX4 mutations-either loss- or gain-of-function-which are a leading cause of childhood-onset PAH. The clinically heterogeneous TBX4 syndrome can include skeletal anomalies (e.g., small patella syndrome) and developmental lung disease (DEVLD) (Galambos, 2019). TBX4 is expressed in lung mesenchymal cells such as matrix fibroblasts, pericytes, and smooth muscle cells, all contributing to PAH pathogenesis (Karolak, 2023; Maldonado, 2025). Our five patient-derived TBX4-mutant hiPSC lines provide a powerful model to investigate cell-specific mechanisms in HPAH/DEVLD-PH and support precision drug discovery and therapy development targeting TBX4-related abnormalities.
2025-10-21 | Extracellular Vesicles: Multimodal Tools for Diagnosis, Prognosis, and Therapy in Respiratory Diseases.
Respiratory diseases are increasing global health burden with persistently high morbidity and mortality. Extracellular vesicles (EVs), which are virtually released by all cell types and carry a variety of molecules like miRNAs, have emerged as crucial mediators of intercellular communication. They play a key role in maintaining lung homeostasis and are involved in the pathogenesis of various respiratory conditions. Furthermore, mesenchymal stromal cell-derived EVs (MSC-EVs) have shown significant therapeutic potential due to their anti-inflammatory, antimicrobial, and reparative properties. This narrative review critically assesses the current body of literature on the roles of EVs in respiratory diseases. We examine evidence from pre-clinical and clinical studies that investigate EVs as biomarkers and therapeutics for conditions including asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), lung cancer, and pulmonary arterial hypertension (PAH). EVs reflect the physiological or pathological state of their parental cells, making them promising multimodal biomarkers for the early diagnosis and monitoring of disease progression. Additionally, MSC-EVs function as effective, cell-free therapeutic agents. In a variety of disease models, they demonstrate efficacy by modulating immune responses, enhancing alveolar fluid clearance, and restoring epithelial and endothelial barrier integrity, leading to improved survival and outcomes. EVs hold a dual and transformative potential in respiratory medicine. They may serve as valuable diagnostic and prognostic tools, and their application as cell-free therapeutics represents a novel and promising strategy for treating a wide spectrum of debilitating respiratory diseases.
proteins
2026-09-09 | Mechanosensitive Stanniocalcin-1 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation and Attenuates Experimental Pulmonary Hypertension.
Idiopathic pulmonary arterial hypertension (IPAH) is driven by progressive vascular remodeling, particularly smooth muscle cell (SMC) proliferation. Current combination vasodilator therapies have markedly improved outcomes; however, prognosis remains poor in subgroups such as patients with respiratory comorbidities. Elevation of intravascular hydrostatic pressure is a hallmark of IPAH, yet its direct role in pulmonary artery SMCs remains unclear. We aimed to identify pressure-responsive mediators using a newly developed hydrostatic pressurization system to model hypertensive hemodynamics. Pulmonary artery SMCs from 4 patients with IPAH were exposed to high hydrostatic pressure (70/40 mm Hg, 60 bpm). Transcriptomic profiling identified differentially expressed genes, which were validated by quantitative polymerase chain reaction. Functional studies included PIEZO1 (piezo type mechanosensitive ion channel component 1) modulation, rhSTC1 (recombinant human stanniocalcin-1) treatment, bromodeoxyuridine incorporation, and Western blotting for cell-cycle regulators. Chronic hypoxia-induced pulmonary hypertension was assessed in wild-type and Stc1-/- mice by hemodynamic and histological analyses, with or without intratracheal rhSTC1 administration. RNA sequencing revealed STC1 to be a pressure-induced gene in IPAH SMCs. PIEZO1 activation upregulated STC1, whereas knockdown blunted this response. STC1 was upregulated in IPAH lungs, while rhSTC1 reduced pulmonary arterial SMC proliferation and increased p-p53, p21, and p27 expression. Stc1-/- mice under hypoxia exhibited significantly higher right ventricular systolic pressure and greater pulmonary arterial medial thickness than wild-type mice. CD68-positive macrophages were increased in Stc1-/- mice under normoxia and further elevated with hypoxia. Intratracheal administration of rhSTC1 attenuated PAH in wild-type and Stc1-/- mice. Elevated hydrostatic pressure drives STC1 expression via PIEZO1, suggesting an adaptive but insufficient protective response in IPAH. Modulation of STC1 (stanniocalcin-1) may represent a potential therapeutic approach.
2026-09-04 | Observed Weight Gain in Patients With Pulmonary Arterial Hypertension Treated With Sotatercept.
Sotatercept, an activin signaling inhibitor for pulmonary arterial hypertension (PAH), has demonstrated significant improvements in clinical outcomes though its off-target effects are still an area for discovery. Anecdotal increases in total body weight not attributable to fluid retention have been observed. Understanding the potential for weight gain and body composition changes is important as excessive weight gain in the PAH population is deleterious whereas increases in lean body mass may favorably affect exercise capacity. Therefore, we conducted a single-center retrospective observational cohort study of adult Group 1 PAH patients seen at a Pulmonary Hypertension Association-accredited Comprehensive Care Center treated with sotatercept for a minimum of 12 weeks. The primary endpoint was the proportion of patients who experienced clinically significant weight gain of ≥ 5% with sotatercept treatment. Secondary endpoints were the frequency of sotatercept dose adjustments required due to changes in body weight. Exploratory analyses were conducted to identify potential relationships between weight change and covariates of interest. Of 23 patients included, clinically significant weight gain was observed in 43.5% (n = 10). The median absolute change from baseline weight was 3.18 kg (Q1-Q3, -0.80-7.43 kg), and the median percent change was 4.43 (Q1-Q3, -0.78-9.01). Dosage adjustments based on dosing weight changes (increase or decrease) occurred at an incidence of 1.56 per patient-year. These results suggest the importance of ongoing monitoring of body weight throughout sotatercept treatment and that weight gain is commonly associated with treatment, although not previously observed or evaluated in clinical trials to date.
2026-09-01 | Targeting Novel Pathways in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of New Therapeutic Agents.
Pulmonary arterial hypertension (PAH) is a progressive condition marked by vascular remodelling, increased pulmonary vascular resistance, and right ventricular dysfunction. Current vasodilator therapies fail to reverse disease progression. Alternative molecular pathways may offer improved therapeutic outcomes and potentially modify the disease course. This systematic review and meta-analysis evaluated the efficacy and safety of emerging PAH therapies targeting alternative pathways, including bone morphogenetic protein signalling, rho-kinase inhibition, estrogen modulation, AMP-activated protein kinase activation, phosphodiesterase-5 inhibition, soluble guanylate cyclase stimulation, and regenerative stem cell therapy. A systematic review was performed following PRISMA guidelines. Randomised controlled trials (RCTs) and phase I-III studies assessing novel therapies were included. Primary outcomes were six-minute walk distance (6MWD) and haemodynamic parameters. Secondary endpoints included brain natriuretic peptide (BNP)/N-terminal pro-BNP (NT-proBNP), World Health Organization Functional Class (WHO-FC), tricuspid annular plane systolic excursion (TAPSE), and safety profile. Meta-analysis employed a random-effects model. Thirteen trials (1,782 participants) met inclusion criteria. Sotatercept improved 6MWD, pulmonary vascular resistance (PVR), and NT-proBNP. Riociguat enhanced haemodynamics and WHO-FC. Metformin plus bosentan improved exercise capacity and right ventricular function. Udenafil and fasudil showed modest benefits, while anastrozole had mixed results with possible sex-specific effects. Cardiosphere-derived stem cells showed early promise for right ventricular recovery. Heterogeneity was high across studies. Novel therapies targeting non-vasodilatory pathways show promise in PAH, though pooled estimates were limited by extreme heterogeneity. At the individual trial level, sotatercept (0.7 mg/kg), riociguat (2.5 mg), and metformin (500 mg with bosentan) showed the most favourable benefit profiles. Standardised trial designs and consistent outcome reporting are needed to confirm these potential disease-modifying effects.
2026-07-28 | AMPK/USP10 loop activation of ACE2: implications for pulmonary hypertension.
The intricate balance between angiotensin-converting enzyme 1 (ACE1) and 2 (ACE2) in the pulmonary vasculature is pivotal for the pathogenesis of pulmonary arterial hypertension (PAH). Catalysing the K48-linked deubiquitination, ubiquitin carboxyl-terminal hydrolase 10 (USP10) is involved in tumour suppression, autophagy, and cell proliferation. This study aims to determine whether a positive feedback loop of USP10 and AMP-activated protein kinase (AMPK) in pulmonary endothelium is protective against PAH. In silico data analyses and in vitro culture cell experiments were used to investigate the role of USP10 in human idiopathic PAH (IPAH) and rodent pulmonary hypertension (PH) as well as the underlying mechanism involving a positive feedback loop of AMPK and USP10 in lung endothelium. Endothelial cell (EC)-specific USP10 transgenic (Tg) mice and mice administered liraglutide were used to explore the efficacy of the AMPK/USP10 loop in mitigating PH in rodents. USP10 level was decreased in the lung endothelium of human IPAH and rodent PH. AMPK/USP10 loop activation increased ACE2 Ser-680 phosphorylation and Lys-788 deubiquitination, thus contributing to the homeostatic level of ACE2 and lung vascular patency. Mice with liraglutide administration phenocopied the mitigated PH in EC-specific USP10 Tg mice, in part because of the activated AMPK/USP10 loop in the pulmonary endothelium. Genetic or pharmacologic [via glucagon-like peptide-1 receptor agonists (GLP-1 RAs)] interventions in the AMPK/USP10 loop can augment ACE2 level in lung endothelium. This type of ACE2 enhancement garners protection against PAH in humans and PH in rodents, which provides a rationale for using GLP-1 RAs to alleviate PAH.
2026-06-27 | Off-Label Sotatercept Use in Pediatric Pulmonary Arterial Hypertension: A Single-Center Retrospective Hemodynamic Study.
Sotatercept, a first-in-class activin signaling inhibitor, has demonstrated disease-modifying efficacy in adults with pulmonary arterial hypertension (PAH). Pediatric data remain limited to ongoing clinical trials. We conducted an IRB-approved, single-center retrospective analysis of pediatric patients with WHO Group 1 or Group 3 PAH treated with off-label sotatercept at Rady Children's Hospital / UC San Diego. All patients had received maximal background triple therapy yet demonstrated persistent symptoms or adverse hemodynamics. Right heart catheterization was performed before sotatercept initiation and at approximately 24 weeks thereafter. Hemodynamic parameters were analyzed descriptively. Seven pediatric patients (median age 14 years; range 4-19) were included. Diagnoses comprised idiopathic PAH, heritable PAH, and PAH associated with congenital heart disease or congenital diaphragmatic hernia. Following sotatercept initiation, the majority of patients demonstrated reductions in pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (mPAP), with heterogeneity in magnitude of response. Pulmonary capillary wedge pressure (PCWP) remained stable in all patients. In this small, highly selected pediatric cohort with advanced PAH refractory to triple therapy, off-label sotatercept was associated with favorable hemodynamic trends at 24 weeks. These findings support biologic plausibility suggested by adult randomized trials and underscore the urgent need for prospective pediatric studies.
oligonucleotides
2025-11-01 | Comparative analysis of microRNA expression in idiopathic pulmonary arterial hypertension and Eisenmenger syndrome: Insights into vascular remodeling and disease progression
Abstract Introduction Idiopathic pulmonary arterial hypertension (IPAH) and Eisenmenger syndrome (ES) are distinct forms of pulmonary hypertension marked by progressive vascular remodeling and increased pulmonary vascular resistance. IPAH results from primary vascular dysfunction, whereas ES arises secondary to congenital heart defects with systemic-to-pulmonary shunting. MicroRNAs (miRNAs) regulate angiogenesis, inflammation, and smooth muscle proliferation, offering promise as biomarkers to differentiate these conditions. Objectives To compare miRNA expression profiles in IPAH and ES patients and correlate them with clinical parameters to elucidate vascular remodeling mechanisms and identify potential diagnostic and therapeutic targets. Methods The study enrolled 12 IPAH and 19 ES patients. Clinical data (age, gender, NT-proBNP, and 6-minute walk test [6MWT] distances) were collected. Peripheral blood was obtained, total RNA extracted, and miRNA profiling performed using the TaqMan® Array Human MicroRNA A+B Cards Set (754 miRNAs). Differential expression was analyzed via the ΔΔCt method (normalized to endogenous controls), with Relative Quantification (RQ) calculated as RQ=2^(−ΔΔCt) (where RQ > 1 indicates upregulation; RQ < 1, downregulation). Results Eighteen miRNAs were significantly differentially expressed (fold change >2, p <0.05). In IPAH, there was marked upregulation of pro-proliferative/anti-apoptotic miRNAs (e.g., miR-30a-5p, RQ: 19.1; miR-501, RQ: 21.2; miR-875-5p, RQ: 223.5), while ES patients showed higher expression of miRNAs with anti-inflammatory/endothelial-protective roles (e.g., miR-30e-3p, RQ: 0.44; miR-629, RQ: 0.31; miR-603, RQ: 0.34), with miR-520c-3p markedly downregulated in IPAH (RQ: 0.015). Additionally, miR-378, miR-151-3p, and miR-720 were lower in IPAH. Clinically, the IPAH group (mean age 47 ± 12 years, 67% female) had significantly higher NT-proBNP [median 1800 pg/mL (IQR: 1200–2400)] and reduced 6MWT distances [median 320 m (IQR: 280–360)] compared to ES (mean age 35 ± 10 years, 58% female; NT-proBNP: median 900 pg/mL [IQR: 700–1100]; 6MWT: median 420 m [IQR: 380–460]) (p <0.01 for NT-proBNP and 6MWT; p=0.01 for age; gender NS). Pathway analysis implicated key networks—including TGF-β, HIF-1α, and NF-κB—in mediating these miRNA alterations. Conclusion Distinct miRNA profiles in IPAH and ES correlate with differing clinical characteristics, suggesting divergent molecular mechanisms of vascular remodeling. The upregulation of proliferative miRNAs in IPAH, combined with higher NT-proBNP and lower exercise capacity, contrasts with a more protective miRNA signature in ES—highlighting the potential of miRNA profiling as a diagnostic and therapeutic tool in pulmonary hypertension. Further studies with larger cohorts are warranted.
2025-06-26 | LncRNA-536 and RNA-Binding Protein RBM25 Interactions in Pulmonary Artery Smooth Muscle Cells: Implications in Pulmonary Hypertension.
In this study, we define the mechanistic association between long noncoding RNA: ENST00000495536 (lnc-536) and transcription factor HOXB13 (homeobox B13) in mediating proproliferative smooth muscle phenotype associated with pulmonary hypertension. In vitro knockdown or knockin, along with RNA pull-down and immunoprecipitation studies, were used to evaluate the role of lnc-536 and HOXB13 in regulating pulmonary arterial smooth muscle cell (PASMCs) phenotype. The in vivo role was determined by injecting lnc-536 antisense oligos in pulmonary hypertensive rats. Increased levels of lnc-536 promote the proliferative phenotype of PASMCs by downregulating the expression of the tumor suppressor: HOXB13. Knockdown of lnc-536 and overexpression of HOXB13 in proliferative PASMCs resulted in increased expression of VGLL4 (vestigial-like family member 4), a negative regulator of Hippo and Wnt (Wingless-related integration site) signaling pathways, with a corresponding decrease in TEAD4 (TEA domain family member 1) expression. The lnc-536 pull-down assay and RNA-immunoprecipitation demonstrated the interactions of lnc-536 with RBP (RNA-binding protein): RBM25 (RNA-binding motif 25) and direct interactions of RBM25 with SFPQ (splicing factor proline/glutamine-rich), a transcriptional regulator that has a binding motif on HOXB13. The knockdown of RBM25 in the hyperproliferative PASMCs resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Furthermore, the increased levels of lnc-536 and decreased levels of HOXB13 were observed in PASMCs from idiopathic pulmonary hypertension patients but not in cells from familial pulmonary hypertension patients. We confirmed that lnc-536 contributes to the RBM25-mediated remodeling of the SFPQ-HOXB13 complex in the idiopathic PAH-PASMCs as well. Finally, in vivo inhibition of lnc-536 using GapmeRs (Gapmer antisense oligonucleotides) in Sugen-hypoxia and HIV-transgenic pulmonary hypertension rats prevented the increase in right ventricular systolic pressure, right ventricular hypertrophy/fibrosis, and pulmonary vascular remodeling with a parallel increase in HOXB13 expression in rat PASMCs. Lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to a decrease in HOXB13 expression and hyperproliferation of smooth muscle cells by potentially regulating Wnt and Hippo signaling associated with PAH development.
2024-10-03 | lncRNA VELRP Modulates Pulmonary Arterial Smooth Muscle Cell Proliferation and Promotes Vascular Remodeling in Pulmonary Hypertension.
Pulmonary hypertension is a devastating vascular disorder characterized by extensive pulmonary vascular remodeling, ultimately leading to right ventricular failure and death. Activation of PDGF (platelet-derived growth factor) signaling promotes the hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs), thus contributing to the pulmonary vascular remodeling. However, the molecular mechanisms that govern hyperproliferation of PASMCs induced by PDGF remain largely unknown, including the contribution of long noncoding RNAs (lncRNAs). In this study, we aimed to identify a novel lncRNA regulated by PDGF implicated in PASMC proliferation in pulmonary vascular remodeling. RNA-sequencing analysis was conducted to identify a novel lncRNA named vessel-enriched lncRNA regulated by PDGF-BB (platelet-derived growth factor-BB; VELRP). Functional investigations of VELRP were performed using knockdown and overexpression strategies along with RNA sequencing. Validation of the function and potential mechanisms of VELRP was performed through Western blot, RNA immunoprecipitation, and chromatin immunoprecipitation assays. We identified a novel vessel-enriched lncRNA with an increased response to PDGF-BB stimulus. VELRP was identified as an evolutionarily conserved RNA molecule. Modulation of VELRP in PASMCs significantly altered cell proliferation. Mechanistically, VELRP enhances trimethylation of H3K4 (histone H3 lysine 4) by interacting with WDR5 (WD repeat-containing protein 5), leading to increased expression of CDK (cyclin-dependent kinase) 1, CDK2, and CDK4 and consequent hyperproliferation of PASMCs. The pathological relevance of VELRP upregulation in pulmonary artery was confirmed using rat pulmonary hypertension models in vivo, as well as in PASMCs from patients with idiopathic pulmonary arterial hypertension. Specific knockdown of VELRP in smooth muscle cells using adeno-associated virus type 9 SM22α (smooth muscle protein 22α) promoter-shRNA-mediated silencing of VELRP resulted in a significant decrease in right ventricular systolic pressure and vascular remodeling in rat pulmonary hypertension model. VELRP, as an lncRNA upregulated by PDGF-BB, mediates PASMC proliferation via WDR5/CDK signaling. In vivo studies demonstrate that targeted intervention of VELRP in smooth muscle cells can prevent the development of pulmonary hypertension.
2024-09-10 | LncRNA-536 and RNA Binding Protein RBM25 Interactions in Pulmonary Arterial Hypertension.
Hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the essential features of the maladaptive inward remodeling of the pulmonary arteries in pulmonary arterial hypertension (PAH). In this study, we define the mechanistic association between long-noncoding RNA: ENST00000495536 (Lnc-536) and anti-proliferative HOXB13 in mediating smooth muscle hyperplasia. Antisense oligonucleotide-based GapmeRs or plasmid overexpressing lnc-536 were used to evaluate the role of lnc-536 in mediating hyperproliferation of PDGF-treated or idiopathic PAH (IPAH) PASMCs. Further, we pulled down lnc536 to identify the proteins directly interacting with lnc536. The in-vivo role of lnc-536 was determined in Sugen-hypoxia and HIV-transgenic pulmonary hypertensive rats. Increased levels of lnc-536 in PDGF-treated or IPAH PASMCs promote hyperproliferative phenotype by downregulating the HOXB13 expression. Knockdown of lnc-536 in-vivo prevented increased RVSP, Fulton Index, and pulmonary vascular remodeling in Sugen-Hypoxia rats. The lncRNA-536 pull-down assay demonstrated the interactions of RNA binding protein: RBM25 with SFPQ, a transcriptional regulator that has a binding motif on HOXB13 exon Further, The RNA-IP experiment using the SFPQ antibody showed direct interaction of RBM25 with SFPQ and knockdown of RBM25 resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Finally, we examined the role of lnc-536 and HOXB13 axis in the PASMCs exposed to the dual hit of HIV and a stimulant: cocaine as well. lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to the decrease in HOXB13 expression and hyperproliferation of smooth muscle cells associated with PAH development.
2024-08-24 | MFN2-dependent mitochondrial dysfunction contributes to Relm-β-induced pulmonary arterial hypertension via USP18/Twist1/miR-214 pathway.
Induction of resistin-like molecule β (Relm-β) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-β regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-β promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-β increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-β was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-β receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-β promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH.
other
2026-09-24 | Integrated Metabolic and Immune Molecular Subtyping and a Molecular Classification Score for Revealing Disease Heterogeneity in Pulmonary Arterial Hypertension.
Despite the central role of metabolic-immune crosstalk in pulmonary arterial hypertension (PAH), integrative quantitative tools remain lacking. We aimed to construct and validate a metabolic-immune molecular classification score (MIRS) as a quantitative metric to capture the inflammation-metabolism balance and to assess its discriminatory performance for molecular subtyping, cross-cohort applicability, and biological implications. We integrated five PAH lung tissue transcriptomic datasets from the Gene Expression Omnibus (GEO). A training set was used to identify differentially expressed genes and to derive MIRS as the first principal component of 20 core genes. MIRS was projected onto independent validation cohorts. Immune microenvironment, pathway activities, protein-protein interaction, and drug repositioning analyses were performed. MIRS significantly distinguished Non-IPAH from IPAH in GSE117261 (AUC = 0.718, p = 0.010) and revealed internal heterogeneity in SSc-PAH. MIRS-related gene expression patterns showed significant differences across COPD and ILD lung tissues in independent datasets. A unified fixed PCA projection pipeline with mean imputation for missing core genes was applied to all pulmonary disease datasets, enabling consistent numerical quantification of MIRS across cohorts under the same mathematical framework. MIRS failed to discriminate PAH from controls in PBMCs, indicating that this tissue-derived signature is not readily detectable in peripheral blood-a limitation that restricts its applicability to lung tissue specimens and highlights challenges for blood-based biomarker development in PAH. Higher MIRS correlated with increased immune scores and myeloid cell infiltration in Non-IPAH. Drug prediction identified sirolimus and tocilizumab as top candidates, with MIRS-stratified sensitivity patterns aligning with pathway loading directions. MIRS is a quantitative, tissue-restricted metric that captures metabolic-immune activation in PAH, with exploratory observations in other pulmonary diseases that warrant further validation. It provides a molecular stratification basis for subtype discrimination and a hypothesis-generating framework for future therapeutic investigations.
2026-09-07 | Vascular smooth muscle cell-derived osteoprotegerin drives pulmonary arterial hypertension via AKT activation and is attenuated by monoclonal antibody therapy.
Pulmonary arterial hypertension (PAH) is driven by sustained vasoconstriction and structural remodelling of distal pulmonary arteries. We have previously demonstrated that osteoprotegerin (OPG, tnfrsf11b) is upregulated in PAH animal models and patient tissues, with circulating levels being prognostic. OPG knockout mice exhibit an attenuated PAH phenotype, and therapeutic inhibition using a human monoclonal anti-OPG antibody reduces disease severity in multiple rodent models. However, the key cellular source of pathogenic OPG and the mechanism underlying therapeutic blockade remain unknown. To define the main cellular source of OPG, conditional Tnfrsf11b deletion was generated by crossing OPGfl/fl mice with PGKcretg/+ (global), LysMcretg/+ (myeloid), Myl2cretg/+ (cardiac myocytes), Cdh5cretg/+ (endothelial cells, ECs), smMHCcretg/+ (VSMCs), Col1a2cretg/+ (fibroblasts, FBs). Knockouts were induced by tamoxifen injection, and PAH established using Sugen5416/hypoxia (SuHx) model. Cardiopulmonary phenotyping included echocardiography, cardiac catheterisation, and histological analysis. Mechanistic studies were performed in VSMCs using peptide-based kinase activity profiling (PamStation).PGKcretg/+/OPGfl/fl mice phenocopied the previous results obtained with global OPG knockout (OPG-/-). Only VSMC-specific deletion (smMHCcretg/0/OPGfl/fl) resulted in significantly improved haemodynamic parameters, evidenced by reduced RVSP and pulmonary vascular resistance (PVR), and reduced pulmonary vascular remodelling demonstrating that VSMC-derived OPG is the primary driver of PAH pathogenesis.Kinome profiling of control and IPAH-PASMCs treated with OPG +/- anti-OPG antibody revealed IPAH specific regulation of PI3K-Akt and enrichment of pathways involving autophagy, and longevity regulation linked to cellular stress resistance and growth. Anti-OPG antibody treatment reduced AKT phosphorylation in IPAH PASMCs. Knock-down of AKT1 by siRNA reduced OPG-induced proliferation and migration of human PASMC. These results align with emerging data implicating OPG in cellular senescence and vascular aging. Together, these findings highlight VSMC-derived OPG as a critical mediator of pulmonary vascular remodelling in PAH pathogenesis and suggest that targeting OPG via a therapeutic antibody is mediated through PI3K-Akt signalling.
2026-07-02 | Alterations in the fecal virome and bacteriome-virome interplay in IPAH.
Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening cardiovascular disorder characterized by complex multisystem disturbances. Although alterations in the gut microbiota have been reported in IPAH, how the gut virome interacts with bacterial communities and host metabolism remains unclear. We enrolled 28 patients with IPAH and 30 age-matched healthy controls (HCs). Fecal viromes and bacteriomes were profiled by metagenomic sequencing, and serum metabolomic data were integrated to construct virus-bacterium-metabolite interaction networks. Random forest models were used to evaluate the diagnostic potential of virome features. IPAH patients exhibited markedly reduced gut virome diversity (Shannon, Simpson, and Pielou indices, p < 0.05) and distinct community structures from HCs (p < 0.01). A total of 499 differential viral operational taxonomic units (vOTUs) were identified, accompanied by extensive reorganization of interaction networks. At the phylum level, Hofneiviricota was enriched and Phixviricota depleted, both correlating with clinical indicators. Virus-bacterium associations were markedly increased in IPAH (44,894 vs. 17,920, r > 0.5). Notably, vOTU2967, vOTU1924, and vOTU4522 were elevated and inversely related to Bacteroides, whose depletion was associated with increased lactic acid levels. Mediation analysis confirmed significant indirect virus-bacterium-metabolite effects (p < 0.05). Random forest models based on vOTUs or viral families effectively distinguished IPAH patients from controls, highlighting the exploratory potential of gut virome features for mechanistic insights. IPAH is characterized by reduced virome diversity, altered viral taxa, and reorganized virus-bacterium-metabolite networks. These findings suggest that gut viruses may influence disease progression by modulating bacterial metabolism, providing a potential avenue for biomarker discovery and therapeutic intervention.
2026-06-18 | Pulmonary arterial hypertension from a translational perspective: Bridging pathophysiology and treatment.
Pulmonary arterial hypertension (PAH) is a rare, progressive disorder defined by elevated pulmonary arterial pressure and vascular resistance, ultimately leading to right ventricular failure and premature death. Once considered a disease of pure vasoconstriction, PAH is now recognized as a complex vasculopathy involving endothelial dysfunction, inflammation, metabolic dysregulation, and genetic susceptibility. The pulmonary vasculature is dynamically narrowed by vasoconstriction, structurally obstructed by smooth muscle and endothelial proliferation, and pathologically stiffened by fibrosis and extracellular matrix deposition. Multiple cell types including endothelial cells, smooth muscle cells, fibroblasts, and immune cells contribute to this remodeling process. At the molecular level, hyperproliferative, apoptosis-resistant phenotypes emerge through mitochondrial dysfunction, oxidative stress, and endothelial-to-mesenchymal transition, which together drive a Warburg-like metabolic shift favoring glycolysis over oxidative phosphorylation. Chronic immune activation, characterized by cytokine release, T-cell and macrophage infiltration, and disrupted immune regulation, further amplifies vascular injury. Genetic studies have identified mutations in BMPR2, TBX4, SOX17 , and other regulators of the bone morphogenic protein (BMP)/transform-ing growth factor-β (TGF-β) pathway as key contributors to heritable and idiopathic forms of PAH, highlighting impaired endothelial repair and aberrant signaling as central mechanisms. Recent translational breakthroughs have yielded novel therapeutic strategies beyond traditional vasodilators. Agents targeting the BMP/TGF-β axis (e.g., sotatercept), growth factor signaling (seralutinib), inflammatory pathways (tocilizumab, rituximab), and metabolic remodeling (pyruvate dehydrogenase kinases [PDK] and fatty acid oxidation [FAO] modulators) are redefining treatment paradigms. Concurrently, large-scale multi-omics initiatives such as PVDOMICS and PHOENIKS enable deep phenotyping, which unravels molecular endotypes and informs precision medicine approaches. This review summarizes the pathophysiology of PAH and the ongoing clinical trials in the PAH field.
2026-05-06 | Neutrophil extracellular traps-related biomarkers in idiopathic pulmonary arterial hypertension: A machine learning-based identification and experimental validation study.
Neutrophil extracellular traps (NETs) are increasingly recognized as critical mediators in vascular inflammation and remodeling, yet their molecular mechanisms in idiopathic pulmonary arterial hypertension (IPAH) pathogenesis remain largely unexplored. This study employed integrated bioinformatics approaches and experimental validation to identify NETs-related biomarkers in IPAH. We performed weighted gene co-expression network analysis (WGCNA) on merged transcriptomic datasets (GSE117261 and GSE48149, comprising 40 IPAH and 34 control samples), identifying a blue module significantly correlated with IPAH status. By intersecting module genes with 69 known NETs-related genes, we obtained 19 differentially expressed NETs-related genes (DE-NRGs) enriched in neutrophil degranulation, interleukin-6 regulation, and NETs formation pathways. Three complementary machine learning algorithms converged on five key biomarkers: CSF3R, MGAM, ITGAM, TLR8 (downregulated), and SELP (upregulated). These biomarkers demonstrated strong diagnostic performance in an independent validation cohort, with an area under the curve greater than 0.8. Immune infiltration analysis revealed significantly decreased neutrophils, macrophages, and myeloid-derived suppressor cells in IPAH patients. Single-cell RNA sequencing validated cell-type-specific expression patterns, with CSF3R predominantly in neutrophils, ITGAM/TLR8 in macrophages, and SELP in endothelial cells. Critically, monocrotaline-induced rat pulmonary arterial hypertension model confirmed significant downregulation of MGAM, CSF3R and ITGAM at protein levels. Our findings establish a NETs-related molecular signature for IPAH diagnosis and reveal impaired neutrophil function as a key pathogenic mechanism in IPAH, providing novel molecular targets for therapeutic intervention and risk stratification.
small molecules
2026-09-29 | Effect of supplemental oxygen therapy on 6-min walk distance in patients with pulmonary arterial hypertension living at 2850 m: a randomised, crossover trial.
Patients with pulmonary arterial hypertension (PAH) who permanently live at high altitude (>2500 m) face particular challenges due to hypobaric hypoxia, which may exacerbate pulmonary hypertension and impair exercise capacity. We therefore investigated the effect of low-dose supplemental oxygen therapy (SOT) on 6-min walk distance (6MWD) in high-altitude residents diagnosed with PAH. Adults diagnosed with PAH who permanently live at >2500 m performed two 6MWD tests, once with SOT (1-2 L·min-1 via nasal cannula provided by a portable back-packed concentrator) and once while breathing ambient air (air) at 2850 m according to a randomised, controlled, crossover trial. The primary outcome was the difference in 6MWD between SOT and air. Secondary outcomes were effects of SOT on heart rate, blood pressure and peripheral oxygen saturation (S pO2 ) and Borg scale. 28 patients (86% women, mean±sd age 45±12 years, resting S pO2 93±3%, mean pulmonary artery pressure 52±16 mmHg, 6MWD at 2850 m 462±100 m) were included. SOT compared to hypoxic air at 2850 m did not improve 6MWD (mean difference -5 m, 95% CI: -24 to 14 m, p=0.576), dyspnoea, leg discomfort or end-exercise S pO2 , but did increase resting S pO2 . In high-altitude residents diagnosed with PAH, low-dose SOT as commonly prescribed via portable concentrator did not improve 6MWD nor dyspnoea perception, most likely due to insufficient flow provided by the concentrator during exercise, further lowered by exertional mouth breathing and the weight of the backpacked concentrator.
2026-09-24 | Long-Term Survival in Pulmonary Arterial Hypertension with Different Etiologies: A Single-Center Experience.
Pulmonary arterial hypertension (PAH) is a progressive disease with variable etiologies and poor prognosis. Long-term outcome data across etiologies remain limited. We retrospectively studied 70 patients with PAH confirmed by right heart catheterization at Kaohsiung Chang Gung Memorial Hospital (2005-2023). Baseline characteristics, World Health Organization (WHO) functional class (FC), 6-minute walk distance, hemodynamics, comorbidities, and treatment regimens were collected. Survival was analyzed using the Kaplan-Meier method. The mean age of the patients was 55 years, and 59% were female. Connective tissue disease (CTD) was the leading etiology (35.7%), followed by idiopathic PAH (24.3%) and congenital heart disease (21.4%). The overall survival rates were 80.9%, 76.6%, and 73.4% at 1, 3, and 5 years, respectively. WHO FC IV at diagnosis was significantly associated with worse survival (p < 0.05). Although patients with CTD-PAH had a numerically lower survival rate compared to other etiologies, the difference did not reach statistical significance. Chronic kidney disease (CKD) and coronary artery disease (CAD) were associated with increased mortality. Combination therapy was associated with numerically higher survival (91.8%, 87.0% and 80.8% at 1, 3 and 5 years, respectively) compared to monotherapy or no therapy, although without statistical significance. Baseline risk stratification using the COMPERA 2.0 four-strata model was significantly associated with survival (p < 0.05). CTD etiology, advanced FC, and comorbid CKD or CAD were associated with a poor prognosis in our cohort of patients with PAH. Combination therapy may improve long-term outcomes.
2026-09-23 | Pulmonary arterial hypertension with signs of venous/capillary involvement in connective tissue diseases: paradigms and paradoxes.
Pulmonary arterial hypertension (PAH) with features of venous and/or capillary involvement, formerly pulmonary veno-occlusive disease (PVOD), represents a rare and severe subset of pulmonary hypertension. While PVOD is typically idiopathic, heritable or drug/toxin-induced, "PVOD-like" features have long been recognised in PAH associated with connective tissue diseases (CTDs), especially systemic sclerosis (SSc). This review synthesises the available evidence on this phenotype, integrating published data with an unreported cohort of 25 patients. Venular remodelling is a frequent histological finding in SSc-PAH lung explants, but high-resolution computed tomography (HRCT) signs of PVOD are inconsistently observed at PAH presentation, reflecting a progression of the lung vasculopathy and/or an unmasking effect of pulmonary vasodilators. Patients often exhibit major functional limitation, profound impairment in gas transfer and severe haemodynamic compromise. Assessing venular involvement in SSc-PAH poses unique challenges, due to possible lung fibrosis on HRCT and differential diagnosis with an occult post-capillary component. Despite the lack of robust evidence, PAH-approved therapies are commonly used, although with caution due to a high risk of pulmonary oedema with pulmonary vasodilators. As these patients also display significant arteriolar involvement, which can benefit from these drugs, dedicated treatment strategies warrant further investigation. Prognosis remains dismal, with a 5-year survival around 45-50%. Similar PVOD-like patterns have also anecdotally been reported in systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, Sjögren syndrome and inflammatory myopathies, with comparable features. Overall, PVOD-like disease in CTD-PAH constitutes a high-risk phenotype with unresolved pathogenic and management challenges, requiring refined patient stratification and improved therapeutic strategies.
2026-09-23 | Iron and the lung: emerging roles of iron metabolism in pulmonary disease pathogenesis and therapy.
Iron is an essential micronutrient, but its redox reactivity also renders it potentially toxic. The lungs are particularly vulnerable to iron-dependent oxidative injury due to continuous exposure to high oxygen tension, environmental particles, and microbial pathogens. Pulmonary iron homeostasis is therefore tightly regulated at systemic, cellular, and local levels through coordinated actions of transferrin, ferritin, ferroportin, hepcidin, and the iron responsive element/iron regulatory protein system. Disruption of these pathways contributes to a broad spectrum of pulmonary diseases. In COPD, asthma, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, infectious lung diseases, and lung cancer, iron dysregulation promotes oxidative stress, ferroptosis, inflammation, aberrant repair, vascular remodelling, or pathogen persistence. Notably, systemic iron deficiency may coexist with local pulmonary iron overload, highlighting the compartmentalised nature of lung iron metabolism. Emerging experimental and clinical evidence suggests that therapeutic manipulation of iron availability through supplementation, chelation or targeting iron-dependent pathways may be beneficial in selected contexts. A deeper mechanistic understanding and improved biomarkers will be essential for developing disease-specific iron-modulating strategies.
2026-09-17 | Proteogenomic Profiling of Idiopathic Pulmonary Arterial Hypertension Identifies Sex-Differential Proteins and Candidate Therapeutic Targets.
Current biomarkers for idiopathic pulmonary arterial hypertension (IPAH) lack disease specificity and provide limited biological insight. We hypothesized that integrating population-based proteomics with genetic evidence would identify robust IPAH-associated proteins relevant to risk stratification, early detection, prognosis, sex differences, and candidate drug-repurposing opportunities. We analyzed 2,918 plasma proteins in 44,137 predominantly European-ancestry UK Biobank participants aged 40-69 years, including 252 incident and 141 prevalent IPAH cases. Proteins associated with IPAH were identified using Cox and logistic regression analyses, prioritized by cis-Mendelian randomization, and assessed through cross-ancestry effect-direction concordance and sensitivity analyses. Unsupervised clustering, nested cross-validated prediction models, and target-drug annotation were used for downstream evaluation. Eighteen proteins showed convergent epidemiological and genetic evidence, and 12 remained supported in cross-ancestry and sensitivity analyses. These proteins defined a high-mortality endotype characterized by vascular and ventricular remodeling. Combined clinical and proteomic models achieved AUCs of 0.779 for incident IPAH and 0.768 for mortality. Proteomic contributions differed by sex, and target-drug annotation identified six drug-linked proteins, highlighting ANXA2-linked Artenimol as a repurposing candidate. Twelve biologically plausible IPAH-associated proteins inform risk stratification, prediction, sex-related characterization, and therapeutic prioritization. Independent multi-ancestry validation and mechanistic studies are warranted.
cell therapies
2026-06-25 | Tracheal Delivery of HO-1-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cells Treats Pulmonary Arterial Hypertension by Enhancing Pulmonary Antioxidant and Anti-inflammatory Responses.
Pulmonary arterial hypertension (PAH) is a life-threatening cardiovascular disease, with current treatments only alleviating symptoms. Mesenchymal stem cells (MSCs) possess immune-regulatory and reparative properties, and HO-1-modified MSCs enhance their anti-inflammatory and antioxidant effects. This study aims to investigate the potential of tracheal delivery of HO-1-modified MSCs for the treatment of PAH. This study first assessed the levels of inflammation and oxidative stress in the lung tissue pathology of donors and IPAH patients, detecting F4/80, IL-6, and the oxidative stress marker 8-OHdG. Subsequently, in MCT-induced rat and hypoxia-exposed mouse models, we evaluated lung tissue sections for HE staining and α-SMA immunohistochemistry, along with antioxidant enzymes (SOD, CAT, GSH) and inflammatory factors (TNF-α, IL-18, IL-6, IL-1β) at 1, 2, 3, 4, and 5 weeks to assess the effects of various treatments. Next, we compared the anti-inflammatory and antioxidant capacities of HO-1-modified MSCs derived from umbilical cord (UC-MSCs) and adipose tissue (AD-MSCs), selecting the best cell intervention strategy. Using in vivo imaging, we assessed the cell homing of intravenously injected cells and drug retention after tracheal delivery. After tracheal delivery of HO-1-MSCs at 3, 4, and 5 weeks, we analyzed IHC staining for α-SMA, right heart catheterization, lung tissue inflammation, and antioxidant stress markers to identify the optimal intervention window. The efficacy was also compared with traditional HO-1 pharmacological agonists. Finally, the effects of HO-1-MSCs on vascular cells (PAECs, PASMCs) and immune cells (myeloid-derived/macrophage, myeloid-derived neutrophils) in vivo were further explored to evaluate their potential and mechanisms in PAH treatment. Compared to donor controls, IPAH patient lung tissues exhibited significant inflammation and oxidative stress, with increased macrophage infiltration and elevated levels of IL-6 and 8-OHdG. In MCT rat and hypoxia mouse models, PAH development was associated with vascular remodeling, persistent inflammation, and oxidative stress. UC-MSCs showed stronger anti-inflammatory and antioxidant effects than AD-MSCs. Tracheal delivery of HO-1-MSCs significantly improved outcomes at weeks 3 and 4, reversing pulmonary vascular remodeling, reducing pulmonary artery pressure, inhibiting IL-6 and IL-18 expression, and restoring antioxidant enzyme activity (SOD and CAT). Compared to traditional HO-1 agonists, HO-1-MSCs demonstrated superior efficacy. Additionally, HO-1-MSCs effectively inhibited PAEC proliferation, suppressed the activation of the ERK/AKT pathway, reduced smooth muscle cell proliferation and migration, significantly decreased neutrophil activation, and promoted M2 macrophage polarization while reducing the M1 macrophage population. Tracheal delivery of HO-1-(UC)-MSCs effectively alleviates inflammation and oxidative stress in PAH, improves vascular remodeling and pulmonary artery pressure, and offers a promising new therapeutic strategy for PAH treatment.
2026-03-09 | Pulmonary Artery Denervation for Refractory Sjögren's Syndrome-Associated Pulmonary Arterial Hypertension: A Case Report of Combined Hemodynamic and Renal Recovery.
A 31-year-old woman with primary Sjögren's syndrome presented with severe pre-capillary pulmonary arterial hypertension (mean pulmonary arterial pressure 51 mmHg, pulmonary vascular resistance 14.7 Wood units) and active renal impairment (24-hour urinary protein 1290 mg). Despite initial immunosuppressive therapy and dual oral PAH-targeted treatment with ambrisentan and tadalafil, she remained at high risk. She subsequently underwent pulmonary artery denervation (PADN) using a 45-mm ablation catheter with 120-second radiofrequency applications at three sites on the main pulmonary artery. At 2-month follow-up, she demonstrated significant symptomatic improvement to WHO functional class I, with a 6-minute walk distance of 320 meters, improved hemodynamics (mean pulmonary arterial pressure 35 mmHg, pulmonary vascular resistance 5.63 Wood units), and a reduced NT-proBNP level of 320 pg/mL, achieving an intermediate-low risk status according to the 2022 ESC/ERS guidelines. Renal function also improved (24-hour urinary protein 158 mg). This case suggests that PADN may be an effective adjunctive interventional strategy for refractory autoimmune PAH, even with concurrent renal involvement, facilitating simultaneous cardiopulmonary and renal recovery.
2026-01-15 | CD19 CAR T-cell therapy for connective tissue disease-associated pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs), including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), mixed connective tissue disease, and inflammatory myositis [1]. Patients with CTD-associated PAH exhibit significantly reduced long-term survival compared to those without PAH [2–6]. The refractory nature of underlying CTDs contributes to progressive clinical deterioration and poor outcomes. Current treatments beyond conventional immunosuppression and pulmonary vasodilators remain limited. Emerging evidence implicates B-cell dysregulation in PAH pathogenesis [7, 8]. CD19 chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in refractory CTDs, including SSc and SLE [9, 10]. Herein, we report the first successful application of CD19 CAR T-cell therapy in a patient with CTD-associated PAH.
2025-12-17 | Generation of 5 hiPSC lines from pediatric patients with Heritable pulmonary arterial hypertension (HPAH) caused by heterozygous mutations in the TBX4 gene.
Heritable pulmonary arterial hypertension (HPAH) and underlying pulmonary vascular disease (PVD) are often caused by TBX4 mutations-either loss- or gain-of-function-which are a leading cause of childhood-onset PAH. The clinically heterogeneous TBX4 syndrome can include skeletal anomalies (e.g., small patella syndrome) and developmental lung disease (DEVLD) (Galambos, 2019). TBX4 is expressed in lung mesenchymal cells such as matrix fibroblasts, pericytes, and smooth muscle cells, all contributing to PAH pathogenesis (Karolak, 2023; Maldonado, 2025). Our five patient-derived TBX4-mutant hiPSC lines provide a powerful model to investigate cell-specific mechanisms in HPAH/DEVLD-PH and support precision drug discovery and therapy development targeting TBX4-related abnormalities.
2025-10-21 | Extracellular Vesicles: Multimodal Tools for Diagnosis, Prognosis, and Therapy in Respiratory Diseases.
Respiratory diseases are increasing global health burden with persistently high morbidity and mortality. Extracellular vesicles (EVs), which are virtually released by all cell types and carry a variety of molecules like miRNAs, have emerged as crucial mediators of intercellular communication. They play a key role in maintaining lung homeostasis and are involved in the pathogenesis of various respiratory conditions. Furthermore, mesenchymal stromal cell-derived EVs (MSC-EVs) have shown significant therapeutic potential due to their anti-inflammatory, antimicrobial, and reparative properties. This narrative review critically assesses the current body of literature on the roles of EVs in respiratory diseases. We examine evidence from pre-clinical and clinical studies that investigate EVs as biomarkers and therapeutics for conditions including asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), lung cancer, and pulmonary arterial hypertension (PAH). EVs reflect the physiological or pathological state of their parental cells, making them promising multimodal biomarkers for the early diagnosis and monitoring of disease progression. Additionally, MSC-EVs function as effective, cell-free therapeutic agents. In a variety of disease models, they demonstrate efficacy by modulating immune responses, enhancing alveolar fluid clearance, and restoring epithelial and endothelial barrier integrity, leading to improved survival and outcomes. EVs hold a dual and transformative potential in respiratory medicine. They may serve as valuable diagnostic and prognostic tools, and their application as cell-free therapeutics represents a novel and promising strategy for treating a wide spectrum of debilitating respiratory diseases.
proteins
2026-09-09 | Mechanosensitive Stanniocalcin-1 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation and Attenuates Experimental Pulmonary Hypertension.
Idiopathic pulmonary arterial hypertension (IPAH) is driven by progressive vascular remodeling, particularly smooth muscle cell (SMC) proliferation. Current combination vasodilator therapies have markedly improved outcomes; however, prognosis remains poor in subgroups such as patients with respiratory comorbidities. Elevation of intravascular hydrostatic pressure is a hallmark of IPAH, yet its direct role in pulmonary artery SMCs remains unclear. We aimed to identify pressure-responsive mediators using a newly developed hydrostatic pressurization system to model hypertensive hemodynamics. Pulmonary artery SMCs from 4 patients with IPAH were exposed to high hydrostatic pressure (70/40 mm Hg, 60 bpm). Transcriptomic profiling identified differentially expressed genes, which were validated by quantitative polymerase chain reaction. Functional studies included PIEZO1 (piezo type mechanosensitive ion channel component 1) modulation, rhSTC1 (recombinant human stanniocalcin-1) treatment, bromodeoxyuridine incorporation, and Western blotting for cell-cycle regulators. Chronic hypoxia-induced pulmonary hypertension was assessed in wild-type and Stc1-/- mice by hemodynamic and histological analyses, with or without intratracheal rhSTC1 administration. RNA sequencing revealed STC1 to be a pressure-induced gene in IPAH SMCs. PIEZO1 activation upregulated STC1, whereas knockdown blunted this response. STC1 was upregulated in IPAH lungs, while rhSTC1 reduced pulmonary arterial SMC proliferation and increased p-p53, p21, and p27 expression. Stc1-/- mice under hypoxia exhibited significantly higher right ventricular systolic pressure and greater pulmonary arterial medial thickness than wild-type mice. CD68-positive macrophages were increased in Stc1-/- mice under normoxia and further elevated with hypoxia. Intratracheal administration of rhSTC1 attenuated PAH in wild-type and Stc1-/- mice. Elevated hydrostatic pressure drives STC1 expression via PIEZO1, suggesting an adaptive but insufficient protective response in IPAH. Modulation of STC1 (stanniocalcin-1) may represent a potential therapeutic approach.
2026-09-04 | Observed Weight Gain in Patients With Pulmonary Arterial Hypertension Treated With Sotatercept.
Sotatercept, an activin signaling inhibitor for pulmonary arterial hypertension (PAH), has demonstrated significant improvements in clinical outcomes though its off-target effects are still an area for discovery. Anecdotal increases in total body weight not attributable to fluid retention have been observed. Understanding the potential for weight gain and body composition changes is important as excessive weight gain in the PAH population is deleterious whereas increases in lean body mass may favorably affect exercise capacity. Therefore, we conducted a single-center retrospective observational cohort study of adult Group 1 PAH patients seen at a Pulmonary Hypertension Association-accredited Comprehensive Care Center treated with sotatercept for a minimum of 12 weeks. The primary endpoint was the proportion of patients who experienced clinically significant weight gain of ≥ 5% with sotatercept treatment. Secondary endpoints were the frequency of sotatercept dose adjustments required due to changes in body weight. Exploratory analyses were conducted to identify potential relationships between weight change and covariates of interest. Of 23 patients included, clinically significant weight gain was observed in 43.5% (n = 10). The median absolute change from baseline weight was 3.18 kg (Q1-Q3, -0.80-7.43 kg), and the median percent change was 4.43 (Q1-Q3, -0.78-9.01). Dosage adjustments based on dosing weight changes (increase or decrease) occurred at an incidence of 1.56 per patient-year. These results suggest the importance of ongoing monitoring of body weight throughout sotatercept treatment and that weight gain is commonly associated with treatment, although not previously observed or evaluated in clinical trials to date.
2026-09-01 | Targeting Novel Pathways in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of New Therapeutic Agents.
Pulmonary arterial hypertension (PAH) is a progressive condition marked by vascular remodelling, increased pulmonary vascular resistance, and right ventricular dysfunction. Current vasodilator therapies fail to reverse disease progression. Alternative molecular pathways may offer improved therapeutic outcomes and potentially modify the disease course. This systematic review and meta-analysis evaluated the efficacy and safety of emerging PAH therapies targeting alternative pathways, including bone morphogenetic protein signalling, rho-kinase inhibition, estrogen modulation, AMP-activated protein kinase activation, phosphodiesterase-5 inhibition, soluble guanylate cyclase stimulation, and regenerative stem cell therapy. A systematic review was performed following PRISMA guidelines. Randomised controlled trials (RCTs) and phase I-III studies assessing novel therapies were included. Primary outcomes were six-minute walk distance (6MWD) and haemodynamic parameters. Secondary endpoints included brain natriuretic peptide (BNP)/N-terminal pro-BNP (NT-proBNP), World Health Organization Functional Class (WHO-FC), tricuspid annular plane systolic excursion (TAPSE), and safety profile. Meta-analysis employed a random-effects model. Thirteen trials (1,782 participants) met inclusion criteria. Sotatercept improved 6MWD, pulmonary vascular resistance (PVR), and NT-proBNP. Riociguat enhanced haemodynamics and WHO-FC. Metformin plus bosentan improved exercise capacity and right ventricular function. Udenafil and fasudil showed modest benefits, while anastrozole had mixed results with possible sex-specific effects. Cardiosphere-derived stem cells showed early promise for right ventricular recovery. Heterogeneity was high across studies. Novel therapies targeting non-vasodilatory pathways show promise in PAH, though pooled estimates were limited by extreme heterogeneity. At the individual trial level, sotatercept (0.7 mg/kg), riociguat (2.5 mg), and metformin (500 mg with bosentan) showed the most favourable benefit profiles. Standardised trial designs and consistent outcome reporting are needed to confirm these potential disease-modifying effects.
2026-07-28 | AMPK/USP10 loop activation of ACE2: implications for pulmonary hypertension.
The intricate balance between angiotensin-converting enzyme 1 (ACE1) and 2 (ACE2) in the pulmonary vasculature is pivotal for the pathogenesis of pulmonary arterial hypertension (PAH). Catalysing the K48-linked deubiquitination, ubiquitin carboxyl-terminal hydrolase 10 (USP10) is involved in tumour suppression, autophagy, and cell proliferation. This study aims to determine whether a positive feedback loop of USP10 and AMP-activated protein kinase (AMPK) in pulmonary endothelium is protective against PAH. In silico data analyses and in vitro culture cell experiments were used to investigate the role of USP10 in human idiopathic PAH (IPAH) and rodent pulmonary hypertension (PH) as well as the underlying mechanism involving a positive feedback loop of AMPK and USP10 in lung endothelium. Endothelial cell (EC)-specific USP10 transgenic (Tg) mice and mice administered liraglutide were used to explore the efficacy of the AMPK/USP10 loop in mitigating PH in rodents. USP10 level was decreased in the lung endothelium of human IPAH and rodent PH. AMPK/USP10 loop activation increased ACE2 Ser-680 phosphorylation and Lys-788 deubiquitination, thus contributing to the homeostatic level of ACE2 and lung vascular patency. Mice with liraglutide administration phenocopied the mitigated PH in EC-specific USP10 Tg mice, in part because of the activated AMPK/USP10 loop in the pulmonary endothelium. Genetic or pharmacologic [via glucagon-like peptide-1 receptor agonists (GLP-1 RAs)] interventions in the AMPK/USP10 loop can augment ACE2 level in lung endothelium. This type of ACE2 enhancement garners protection against PAH in humans and PH in rodents, which provides a rationale for using GLP-1 RAs to alleviate PAH.
2026-06-27 | Off-Label Sotatercept Use in Pediatric Pulmonary Arterial Hypertension: A Single-Center Retrospective Hemodynamic Study.
Sotatercept, a first-in-class activin signaling inhibitor, has demonstrated disease-modifying efficacy in adults with pulmonary arterial hypertension (PAH). Pediatric data remain limited to ongoing clinical trials. We conducted an IRB-approved, single-center retrospective analysis of pediatric patients with WHO Group 1 or Group 3 PAH treated with off-label sotatercept at Rady Children's Hospital / UC San Diego. All patients had received maximal background triple therapy yet demonstrated persistent symptoms or adverse hemodynamics. Right heart catheterization was performed before sotatercept initiation and at approximately 24 weeks thereafter. Hemodynamic parameters were analyzed descriptively. Seven pediatric patients (median age 14 years; range 4-19) were included. Diagnoses comprised idiopathic PAH, heritable PAH, and PAH associated with congenital heart disease or congenital diaphragmatic hernia. Following sotatercept initiation, the majority of patients demonstrated reductions in pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (mPAP), with heterogeneity in magnitude of response. Pulmonary capillary wedge pressure (PCWP) remained stable in all patients. In this small, highly selected pediatric cohort with advanced PAH refractory to triple therapy, off-label sotatercept was associated with favorable hemodynamic trends at 24 weeks. These findings support biologic plausibility suggested by adult randomized trials and underscore the urgent need for prospective pediatric studies.
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2025-11-01 | Comparative analysis of microRNA expression in idiopathic pulmonary arterial hypertension and Eisenmenger syndrome: Insights into vascular remodeling and disease progression
Abstract Introduction Idiopathic pulmonary arterial hypertension (IPAH) and Eisenmenger syndrome (ES) are distinct forms of pulmonary hypertension marked by progressive vascular remodeling and increased pulmonary vascular resistance. IPAH results from primary vascular dysfunction, whereas ES arises secondary to congenital heart defects with systemic-to-pulmonary shunting. MicroRNAs (miRNAs) regulate angiogenesis, inflammation, and smooth muscle proliferation, offering promise as biomarkers to differentiate these conditions. Objectives To compare miRNA expression profiles in IPAH and ES patients and correlate them with clinical parameters to elucidate vascular remodeling mechanisms and identify potential diagnostic and therapeutic targets. Methods The study enrolled 12 IPAH and 19 ES patients. Clinical data (age, gender, NT-proBNP, and 6-minute walk test [6MWT] distances) were collected. Peripheral blood was obtained, total RNA extracted, and miRNA profiling performed using the TaqMan® Array Human MicroRNA A+B Cards Set (754 miRNAs). Differential expression was analyzed via the ΔΔCt method (normalized to endogenous controls), with Relative Quantification (RQ) calculated as RQ=2^(−ΔΔCt) (where RQ > 1 indicates upregulation; RQ < 1, downregulation). Results Eighteen miRNAs were significantly differentially expressed (fold change >2, p <0.05). In IPAH, there was marked upregulation of pro-proliferative/anti-apoptotic miRNAs (e.g., miR-30a-5p, RQ: 19.1; miR-501, RQ: 21.2; miR-875-5p, RQ: 223.5), while ES patients showed higher expression of miRNAs with anti-inflammatory/endothelial-protective roles (e.g., miR-30e-3p, RQ: 0.44; miR-629, RQ: 0.31; miR-603, RQ: 0.34), with miR-520c-3p markedly downregulated in IPAH (RQ: 0.015). Additionally, miR-378, miR-151-3p, and miR-720 were lower in IPAH. Clinically, the IPAH group (mean age 47 ± 12 years, 67% female) had significantly higher NT-proBNP [median 1800 pg/mL (IQR: 1200–2400)] and reduced 6MWT distances [median 320 m (IQR: 280–360)] compared to ES (mean age 35 ± 10 years, 58% female; NT-proBNP: median 900 pg/mL [IQR: 700–1100]; 6MWT: median 420 m [IQR: 380–460]) (p <0.01 for NT-proBNP and 6MWT; p=0.01 for age; gender NS). Pathway analysis implicated key networks—including TGF-β, HIF-1α, and NF-κB—in mediating these miRNA alterations. Conclusion Distinct miRNA profiles in IPAH and ES correlate with differing clinical characteristics, suggesting divergent molecular mechanisms of vascular remodeling. The upregulation of proliferative miRNAs in IPAH, combined with higher NT-proBNP and lower exercise capacity, contrasts with a more protective miRNA signature in ES—highlighting the potential of miRNA profiling as a diagnostic and therapeutic tool in pulmonary hypertension. Further studies with larger cohorts are warranted.
2025-06-26 | LncRNA-536 and RNA-Binding Protein RBM25 Interactions in Pulmonary Artery Smooth Muscle Cells: Implications in Pulmonary Hypertension.
In this study, we define the mechanistic association between long noncoding RNA: ENST00000495536 (lnc-536) and transcription factor HOXB13 (homeobox B13) in mediating proproliferative smooth muscle phenotype associated with pulmonary hypertension. In vitro knockdown or knockin, along with RNA pull-down and immunoprecipitation studies, were used to evaluate the role of lnc-536 and HOXB13 in regulating pulmonary arterial smooth muscle cell (PASMCs) phenotype. The in vivo role was determined by injecting lnc-536 antisense oligos in pulmonary hypertensive rats. Increased levels of lnc-536 promote the proliferative phenotype of PASMCs by downregulating the expression of the tumor suppressor: HOXB13. Knockdown of lnc-536 and overexpression of HOXB13 in proliferative PASMCs resulted in increased expression of VGLL4 (vestigial-like family member 4), a negative regulator of Hippo and Wnt (Wingless-related integration site) signaling pathways, with a corresponding decrease in TEAD4 (TEA domain family member 1) expression. The lnc-536 pull-down assay and RNA-immunoprecipitation demonstrated the interactions of lnc-536 with RBP (RNA-binding protein): RBM25 (RNA-binding motif 25) and direct interactions of RBM25 with SFPQ (splicing factor proline/glutamine-rich), a transcriptional regulator that has a binding motif on HOXB13. The knockdown of RBM25 in the hyperproliferative PASMCs resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Furthermore, the increased levels of lnc-536 and decreased levels of HOXB13 were observed in PASMCs from idiopathic pulmonary hypertension patients but not in cells from familial pulmonary hypertension patients. We confirmed that lnc-536 contributes to the RBM25-mediated remodeling of the SFPQ-HOXB13 complex in the idiopathic PAH-PASMCs as well. Finally, in vivo inhibition of lnc-536 using GapmeRs (Gapmer antisense oligonucleotides) in Sugen-hypoxia and HIV-transgenic pulmonary hypertension rats prevented the increase in right ventricular systolic pressure, right ventricular hypertrophy/fibrosis, and pulmonary vascular remodeling with a parallel increase in HOXB13 expression in rat PASMCs. Lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to a decrease in HOXB13 expression and hyperproliferation of smooth muscle cells by potentially regulating Wnt and Hippo signaling associated with PAH development.
2024-10-03 | lncRNA VELRP Modulates Pulmonary Arterial Smooth Muscle Cell Proliferation and Promotes Vascular Remodeling in Pulmonary Hypertension.
Pulmonary hypertension is a devastating vascular disorder characterized by extensive pulmonary vascular remodeling, ultimately leading to right ventricular failure and death. Activation of PDGF (platelet-derived growth factor) signaling promotes the hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs), thus contributing to the pulmonary vascular remodeling. However, the molecular mechanisms that govern hyperproliferation of PASMCs induced by PDGF remain largely unknown, including the contribution of long noncoding RNAs (lncRNAs). In this study, we aimed to identify a novel lncRNA regulated by PDGF implicated in PASMC proliferation in pulmonary vascular remodeling. RNA-sequencing analysis was conducted to identify a novel lncRNA named vessel-enriched lncRNA regulated by PDGF-BB (platelet-derived growth factor-BB; VELRP). Functional investigations of VELRP were performed using knockdown and overexpression strategies along with RNA sequencing. Validation of the function and potential mechanisms of VELRP was performed through Western blot, RNA immunoprecipitation, and chromatin immunoprecipitation assays. We identified a novel vessel-enriched lncRNA with an increased response to PDGF-BB stimulus. VELRP was identified as an evolutionarily conserved RNA molecule. Modulation of VELRP in PASMCs significantly altered cell proliferation. Mechanistically, VELRP enhances trimethylation of H3K4 (histone H3 lysine 4) by interacting with WDR5 (WD repeat-containing protein 5), leading to increased expression of CDK (cyclin-dependent kinase) 1, CDK2, and CDK4 and consequent hyperproliferation of PASMCs. The pathological relevance of VELRP upregulation in pulmonary artery was confirmed using rat pulmonary hypertension models in vivo, as well as in PASMCs from patients with idiopathic pulmonary arterial hypertension. Specific knockdown of VELRP in smooth muscle cells using adeno-associated virus type 9 SM22α (smooth muscle protein 22α) promoter-shRNA-mediated silencing of VELRP resulted in a significant decrease in right ventricular systolic pressure and vascular remodeling in rat pulmonary hypertension model. VELRP, as an lncRNA upregulated by PDGF-BB, mediates PASMC proliferation via WDR5/CDK signaling. In vivo studies demonstrate that targeted intervention of VELRP in smooth muscle cells can prevent the development of pulmonary hypertension.
2024-09-10 | LncRNA-536 and RNA Binding Protein RBM25 Interactions in Pulmonary Arterial Hypertension.
Hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the essential features of the maladaptive inward remodeling of the pulmonary arteries in pulmonary arterial hypertension (PAH). In this study, we define the mechanistic association between long-noncoding RNA: ENST00000495536 (Lnc-536) and anti-proliferative HOXB13 in mediating smooth muscle hyperplasia. Antisense oligonucleotide-based GapmeRs or plasmid overexpressing lnc-536 were used to evaluate the role of lnc-536 in mediating hyperproliferation of PDGF-treated or idiopathic PAH (IPAH) PASMCs. Further, we pulled down lnc536 to identify the proteins directly interacting with lnc536. The in-vivo role of lnc-536 was determined in Sugen-hypoxia and HIV-transgenic pulmonary hypertensive rats. Increased levels of lnc-536 in PDGF-treated or IPAH PASMCs promote hyperproliferative phenotype by downregulating the HOXB13 expression. Knockdown of lnc-536 in-vivo prevented increased RVSP, Fulton Index, and pulmonary vascular remodeling in Sugen-Hypoxia rats. The lncRNA-536 pull-down assay demonstrated the interactions of RNA binding protein: RBM25 with SFPQ, a transcriptional regulator that has a binding motif on HOXB13 exon Further, The RNA-IP experiment using the SFPQ antibody showed direct interaction of RBM25 with SFPQ and knockdown of RBM25 resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Finally, we examined the role of lnc-536 and HOXB13 axis in the PASMCs exposed to the dual hit of HIV and a stimulant: cocaine as well. lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to the decrease in HOXB13 expression and hyperproliferation of smooth muscle cells associated with PAH development.
2024-08-24 | MFN2-dependent mitochondrial dysfunction contributes to Relm-β-induced pulmonary arterial hypertension via USP18/Twist1/miR-214 pathway.
Induction of resistin-like molecule β (Relm-β) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-β regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-β promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-β increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-β was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-β receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-β promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH.
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2026-09-24 | Integrated Metabolic and Immune Molecular Subtyping and a Molecular Classification Score for Revealing Disease Heterogeneity in Pulmonary Arterial Hypertension.
Despite the central role of metabolic-immune crosstalk in pulmonary arterial hypertension (PAH), integrative quantitative tools remain lacking. We aimed to construct and validate a metabolic-immune molecular classification score (MIRS) as a quantitative metric to capture the inflammation-metabolism balance and to assess its discriminatory performance for molecular subtyping, cross-cohort applicability, and biological implications. We integrated five PAH lung tissue transcriptomic datasets from the Gene Expression Omnibus (GEO). A training set was used to identify differentially expressed genes and to derive MIRS as the first principal component of 20 core genes. MIRS was projected onto independent validation cohorts. Immune microenvironment, pathway activities, protein-protein interaction, and drug repositioning analyses were performed. MIRS significantly distinguished Non-IPAH from IPAH in GSE117261 (AUC = 0.718, p = 0.010) and revealed internal heterogeneity in SSc-PAH. MIRS-related gene expression patterns showed significant differences across COPD and ILD lung tissues in independent datasets. A unified fixed PCA projection pipeline with mean imputation for missing core genes was applied to all pulmonary disease datasets, enabling consistent numerical quantification of MIRS across cohorts under the same mathematical framework. MIRS failed to discriminate PAH from controls in PBMCs, indicating that this tissue-derived signature is not readily detectable in peripheral blood-a limitation that restricts its applicability to lung tissue specimens and highlights challenges for blood-based biomarker development in PAH. Higher MIRS correlated with increased immune scores and myeloid cell infiltration in Non-IPAH. Drug prediction identified sirolimus and tocilizumab as top candidates, with MIRS-stratified sensitivity patterns aligning with pathway loading directions. MIRS is a quantitative, tissue-restricted metric that captures metabolic-immune activation in PAH, with exploratory observations in other pulmonary diseases that warrant further validation. It provides a molecular stratification basis for subtype discrimination and a hypothesis-generating framework for future therapeutic investigations.
2026-09-07 | Vascular smooth muscle cell-derived osteoprotegerin drives pulmonary arterial hypertension via AKT activation and is attenuated by monoclonal antibody therapy.
Pulmonary arterial hypertension (PAH) is driven by sustained vasoconstriction and structural remodelling of distal pulmonary arteries. We have previously demonstrated that osteoprotegerin (OPG, tnfrsf11b) is upregulated in PAH animal models and patient tissues, with circulating levels being prognostic. OPG knockout mice exhibit an attenuated PAH phenotype, and therapeutic inhibition using a human monoclonal anti-OPG antibody reduces disease severity in multiple rodent models. However, the key cellular source of pathogenic OPG and the mechanism underlying therapeutic blockade remain unknown. To define the main cellular source of OPG, conditional Tnfrsf11b deletion was generated by crossing OPGfl/fl mice with PGKcretg/+ (global), LysMcretg/+ (myeloid), Myl2cretg/+ (cardiac myocytes), Cdh5cretg/+ (endothelial cells, ECs), smMHCcretg/+ (VSMCs), Col1a2cretg/+ (fibroblasts, FBs). Knockouts were induced by tamoxifen injection, and PAH established using Sugen5416/hypoxia (SuHx) model. Cardiopulmonary phenotyping included echocardiography, cardiac catheterisation, and histological analysis. Mechanistic studies were performed in VSMCs using peptide-based kinase activity profiling (PamStation).PGKcretg/+/OPGfl/fl mice phenocopied the previous results obtained with global OPG knockout (OPG-/-). Only VSMC-specific deletion (smMHCcretg/0/OPGfl/fl) resulted in significantly improved haemodynamic parameters, evidenced by reduced RVSP and pulmonary vascular resistance (PVR), and reduced pulmonary vascular remodelling demonstrating that VSMC-derived OPG is the primary driver of PAH pathogenesis.Kinome profiling of control and IPAH-PASMCs treated with OPG +/- anti-OPG antibody revealed IPAH specific regulation of PI3K-Akt and enrichment of pathways involving autophagy, and longevity regulation linked to cellular stress resistance and growth. Anti-OPG antibody treatment reduced AKT phosphorylation in IPAH PASMCs. Knock-down of AKT1 by siRNA reduced OPG-induced proliferation and migration of human PASMC. These results align with emerging data implicating OPG in cellular senescence and vascular aging. Together, these findings highlight VSMC-derived OPG as a critical mediator of pulmonary vascular remodelling in PAH pathogenesis and suggest that targeting OPG via a therapeutic antibody is mediated through PI3K-Akt signalling.
2026-07-02 | Alterations in the fecal virome and bacteriome-virome interplay in IPAH.
Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening cardiovascular disorder characterized by complex multisystem disturbances. Although alterations in the gut microbiota have been reported in IPAH, how the gut virome interacts with bacterial communities and host metabolism remains unclear. We enrolled 28 patients with IPAH and 30 age-matched healthy controls (HCs). Fecal viromes and bacteriomes were profiled by metagenomic sequencing, and serum metabolomic data were integrated to construct virus-bacterium-metabolite interaction networks. Random forest models were used to evaluate the diagnostic potential of virome features. IPAH patients exhibited markedly reduced gut virome diversity (Shannon, Simpson, and Pielou indices, p < 0.05) and distinct community structures from HCs (p < 0.01). A total of 499 differential viral operational taxonomic units (vOTUs) were identified, accompanied by extensive reorganization of interaction networks. At the phylum level, Hofneiviricota was enriched and Phixviricota depleted, both correlating with clinical indicators. Virus-bacterium associations were markedly increased in IPAH (44,894 vs. 17,920, r > 0.5). Notably, vOTU2967, vOTU1924, and vOTU4522 were elevated and inversely related to Bacteroides, whose depletion was associated with increased lactic acid levels. Mediation analysis confirmed significant indirect virus-bacterium-metabolite effects (p < 0.05). Random forest models based on vOTUs or viral families effectively distinguished IPAH patients from controls, highlighting the exploratory potential of gut virome features for mechanistic insights. IPAH is characterized by reduced virome diversity, altered viral taxa, and reorganized virus-bacterium-metabolite networks. These findings suggest that gut viruses may influence disease progression by modulating bacterial metabolism, providing a potential avenue for biomarker discovery and therapeutic intervention.
2026-06-18 | Pulmonary arterial hypertension from a translational perspective: Bridging pathophysiology and treatment.
Pulmonary arterial hypertension (PAH) is a rare, progressive disorder defined by elevated pulmonary arterial pressure and vascular resistance, ultimately leading to right ventricular failure and premature death. Once considered a disease of pure vasoconstriction, PAH is now recognized as a complex vasculopathy involving endothelial dysfunction, inflammation, metabolic dysregulation, and genetic susceptibility. The pulmonary vasculature is dynamically narrowed by vasoconstriction, structurally obstructed by smooth muscle and endothelial proliferation, and pathologically stiffened by fibrosis and extracellular matrix deposition. Multiple cell types including endothelial cells, smooth muscle cells, fibroblasts, and immune cells contribute to this remodeling process. At the molecular level, hyperproliferative, apoptosis-resistant phenotypes emerge through mitochondrial dysfunction, oxidative stress, and endothelial-to-mesenchymal transition, which together drive a Warburg-like metabolic shift favoring glycolysis over oxidative phosphorylation. Chronic immune activation, characterized by cytokine release, T-cell and macrophage infiltration, and disrupted immune regulation, further amplifies vascular injury. Genetic studies have identified mutations in BMPR2, TBX4, SOX17 , and other regulators of the bone morphogenic protein (BMP)/transform-ing growth factor-β (TGF-β) pathway as key contributors to heritable and idiopathic forms of PAH, highlighting impaired endothelial repair and aberrant signaling as central mechanisms. Recent translational breakthroughs have yielded novel therapeutic strategies beyond traditional vasodilators. Agents targeting the BMP/TGF-β axis (e.g., sotatercept), growth factor signaling (seralutinib), inflammatory pathways (tocilizumab, rituximab), and metabolic remodeling (pyruvate dehydrogenase kinases [PDK] and fatty acid oxidation [FAO] modulators) are redefining treatment paradigms. Concurrently, large-scale multi-omics initiatives such as PVDOMICS and PHOENIKS enable deep phenotyping, which unravels molecular endotypes and informs precision medicine approaches. This review summarizes the pathophysiology of PAH and the ongoing clinical trials in the PAH field.
2026-05-06 | Neutrophil extracellular traps-related biomarkers in idiopathic pulmonary arterial hypertension: A machine learning-based identification and experimental validation study.
Neutrophil extracellular traps (NETs) are increasingly recognized as critical mediators in vascular inflammation and remodeling, yet their molecular mechanisms in idiopathic pulmonary arterial hypertension (IPAH) pathogenesis remain largely unexplored. This study employed integrated bioinformatics approaches and experimental validation to identify NETs-related biomarkers in IPAH. We performed weighted gene co-expression network analysis (WGCNA) on merged transcriptomic datasets (GSE117261 and GSE48149, comprising 40 IPAH and 34 control samples), identifying a blue module significantly correlated with IPAH status. By intersecting module genes with 69 known NETs-related genes, we obtained 19 differentially expressed NETs-related genes (DE-NRGs) enriched in neutrophil degranulation, interleukin-6 regulation, and NETs formation pathways. Three complementary machine learning algorithms converged on five key biomarkers: CSF3R, MGAM, ITGAM, TLR8 (downregulated), and SELP (upregulated). These biomarkers demonstrated strong diagnostic performance in an independent validation cohort, with an area under the curve greater than 0.8. Immune infiltration analysis revealed significantly decreased neutrophils, macrophages, and myeloid-derived suppressor cells in IPAH patients. Single-cell RNA sequencing validated cell-type-specific expression patterns, with CSF3R predominantly in neutrophils, ITGAM/TLR8 in macrophages, and SELP in endothelial cells. Critically, monocrotaline-induced rat pulmonary arterial hypertension model confirmed significant downregulation of MGAM, CSF3R and ITGAM at protein levels. Our findings establish a NETs-related molecular signature for IPAH diagnosis and reveal impaired neutrophil function as a key pathogenic mechanism in IPAH, providing novel molecular targets for therapeutic intervention and risk stratification.
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Drug Discovery Landscape
9 orphan drug designations for Idiopathic pulmonary arterial hypertension.
9 orphan drug designations for Idiopathic pulmonary arterial hypertension.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
prodrug of imatinib | small molecules | FDA | Inhibikase Therapeutics, Inc. | |
treprostinil palmitil | small molecules | FDA | Insmed Incorporated | |
human anti-PDGF-B monoclonal IgG4 antibody | antibodies | FDA | Regeneron Pharmaceuticals, Inc. | |
tetrathiomolybdate | small molecules | FDA | — | Artin Bioscience Inc. |
peroxiredoxin 2 mimetic, a tricyclic compound containing disulfide bond as a pharmacophore | small molecules | FDA | — | Vasthera Co. |
a novel, next-generation, selective ligand trap in the form of a heavy chain fragment (Fc) fusion protein consisting of a modified extracellular domain of the human Activin Type 2B Receptor (ActRIIB) fused to a stabilized human immunoglobulin G4 Fc by a peptide linker. | proteins | FDA | — | AliveGen USA, Inc. |
N-(tert-butylcarbamoyl)-5-cyano-2-((4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)oxy)benzenesulfonamide | small molecules | FDA | — | ATXA Therapeutics Limited |
Macitentan [Opsumit] | small molecules | EMA | Janssen Cilag International | |
Beraprost sodium | small molecules | EMA | IDEA Innovative Drug European Associates (Ireland) Limited |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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