• biomarkers
• echocardiography
• non-invasive screening methods
• pulmonary arterial hypertension
• pulmonary functional tests
• systemic sclerosis

• Humans
• Scleroderma, Systemic/complications
• Scleroderma, Systemic/physiopathology
• Biomarkers/blood
• Biomarkers/analysis
• Mass Screening/methods
• Mass Screening/trends
• Hypertension, Pulmonary/diagnosis
• Hypertension, Pulmonary/etiology
• Natriuretic Peptide, Brain/blood
• Natriuretic Peptide, Brain/analysis
• Pulmonary Arterial Hypertension/diagnosis
• Pulmonary Arterial Hypertension/etiology
• Echocardiography/methods
• Cardiac Catheterization/methods
• Peptide Fragments/blood
• Peptide Fragments/analysis

• Humans
• Calgranulin B/metabolism
• Cardiovascular Diseases/metabolism
• Biomarkers/metabolism
• Inflammation/metabolism
• Animals
• Oxidative Stress

• 82372581 National Natural Science Foundation of China
• 2022JJ30082 Hunan Provincial Natural Science Foundation of China
• W20242007 Health Research Project of Hunan Provincial Health Commission
• National Natural Science Foundation of China

• ILD
• PAH
• SSc
• predictability
• sRAGE
• scleroderma

• Mixed connective tissue disease
• ascites
• pulmonary arterial hypertension
• systemic lupus erythematosus
• systemic sclerosis

• Ascites/diagnosis
• Ascites/drug therapy
• Ascites/etiology
• Epoprostenol/therapeutic use
• Female
• Humans
• Hypertension, Pulmonary/diagnosis
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/etiology
• Middle Aged
• Mixed Connective Tissue Disease/complications
• Vasodilator Agents/therapeutic use

Objective: Regulatory T cells (Tregs) are critical immune modulators to maintain immune homeostasis and limit pulmonary hypertension (PH). This study was aimed to identify Treg-related genes (TRGs) in PH.

Methods: The gene expression profile from lungs of PH patients was retrieved from the Gene Expression Omnibus (GEO) database. The abundance of Tregs was estimated by the xCell algorithm, the correlation of which with differentially expressed genes (DEGs) was performed. DEGs with a |Pearson correlation coefficient| >0.4 were identified as TRGs. Functional annotation and the protein–protein interaction (PPI) network were analyzed. A gene signature for 25 hub TRGs (TRGscore) was generated by a single sample scoring method to determine its accuracy to distinguish PH from control subjects. TRGs were validated in datasets of transcriptional profiling of PH cohorts and in lung tissues of experimental PH mice.

Results: A total of 819 DEGs were identified in lungs of 58 PAH patients compared to that of 25 control subjects of dataset GSE117261. In total, 165 of all these DEGs were correlated with the abundance of Tregs and identified as TRGs, with 90 upregulated genes and 75 downregulated genes compared to that of control subjects. The upregulated TRGs were enriched in negative regulation of multiple pathways, such as cAMP-mediated signaling and I-kappaB kinase/NF-kappaB signaling, and regulated by multiple genes encoding transcriptional factors including HIF1A. Furthermore, 25 hub genes categorized into three clusters out of 165 TRGs were derived, and we identified 27 potential drugs targeting 10 hub TRGs. The TRGscore based on 25 hub TRGs was higher in PH patients and could distinguish PH from control subjects (all AUC >0.7). Among them, 10 genes including NCF2, MNDA/Ifi211, HCK, FGR, CSF3R, AQP9, S100A8, G6PD/G6pdx, PGD, and TXNRD1 were significantly reduced in lungs of severe PH patients of dataset GSE24988 as well as in lungs of hypoxic PH mice compared to corresponding controls.

Conclusion: Our finding will shed some light on the Treg-associated therapeutic targets in the progression of PH and emphasize on TRGscore as a novel indicator for PH.

• Treg-related genes
• gene indicators
• immune
• pulmonary hypertension
• regulatory T cells
• transcriptomics

Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. PAH is characterized by pulmonary artery remodeling, elevated right ventricular pressure (RVP) and, ultimately, cardiac failure. Pulmonary endothelial cells can sense danger or damage caused by mechanical injury or pathogens through alarmin cytokines. These cytokines can signal proliferation to restore barrier integrity or aberrant hyperproliferation and remodeling. We hypothesized that IL‐33 signals pulmonary artery endothelial cells to proliferate under hypertensive conditions during the remodeling response and rise in RVP. To test this hypothesis, pulmonary hypertension (PH) was induced in C57Bl/6J, IL‐33 receptor gene deleted (ST2^−/−) and MYD88 gene deleted (MYD88^−/−) mice by exposure to 10% O₂ and SU5416 injections (SUHX). RVP, arterial wall thickness, endothelial cell proliferation and IL‐33 levels and signaling were evaluated. In response to SUHX. RVP increased in C57Bl/6J mice in response to SUHX (49% male and 70% female; p < 0.0001) and this SUHX response was attenuated in ST2^−/− mice (29% male p = 0.003; 30% female p = 0.001) and absent in MYD88^−/− mice. Wall thickness was increased in SUHX C57Bl/6J mice (p = 0.005), but not in ST2^−/− or MYD88^−/− mice. Proliferating cells were detected in C57Bl/6J mice by flow cytometry (CD31⁺/BrDU⁺; p = 0.02) and immunofluorescence methods (Ki‐67+). IL‐33 was increased by SUHX (p = 0.03) but a genotype effect was not observed (p = 0.76). We observed that in hPAECs, IL‐33 expression is regulated by both IL‐33 and DLL4. These data suggest IL‐33/ST2 signaling is essential for the endothelial cell proliferative response in PH.

• endothelial cells
• interleukin-33 receptor
• pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive condition with an unmet need for early diagnosis, better monitoring, and risk stratification. The receptor for advanced glycation end products (RAGE) is activated in response to hypoxia and vascular injury, and is associated with inflammation, cell proliferation and migration in PAH. For the adult cohort, we recruited 120 patients with PAH, 83 with idiopathic PAH (IPAH) and 37 with connective tissue disease-associated PAH (CTD-PAH), and 48 controls, and determined potential plasma biomarkers by enzyme-linked immunoassay. The established heart failure marker NTproBNP and IL-6 plasma levels were several-fold higher in both adult IPAH and CTD-PAH patients versus controls. Plasma soluble RAGE (sRAGE) was elevated in IPAH patients (3044 ± 215.2 pg/mL) and was even higher in CTD-PAH patients (3332 ± 321.6 pg/mL) versus controls (1766 ± 121.9 pg/mL; p < 0.01). All three markers were increased in WHO functional class II+III PAH versus controls (p < 0.001). Receiver-operating characteristic analysis revealed that sRAGE has diagnostic accuracy comparable to prognostic NTproBNP, and even outperforms NTproBNP in the distinction of PAH FC I from controls. Lung tissue RAGE expression was increased in IPAH versus controls (mRNA) and was located predominantly in the PA intima, media, and inflammatory cells in the perivascular space (immunohistochemistry). In the pediatric cohort, plasma sRAGE concentrations were higher than in adults, but were similar in PH (n = 10) and non-PH controls (n = 10). Taken together, in the largest adult sRAGE PAH study to date, we identify plasma sRAGE as a sensitive and accurate PAH biomarker with better performance than NTproBNP in the distinction of mild PAH from controls.

• RV hypertrophy
• biomarker
• inflammation
• proliferation
• pulmonary arterial hypertension
• soluble receptor for advanced glycation end products (sRAGE)
• vascular injury

• Adult
• Aged
• Aged, 80 and over
• Biomarkers/blood
• Case-Control Studies
• Female
• Germany
• Humans
• Male
• Middle Aged
• Prognosis
• Pulmonary Arterial Hypertension/blood
• Pulmonary Arterial Hypertension/diagnosis
• Receptor for Advanced Glycation End Products/blood
• Sensitivity and Specificity
• Solubility
• Young Adult

The outbreak of coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 and type 2 diabetes (T2D) have now merged into an ongoing global syndemic that is threatening the lives of millions of people around the globe. For this reason, there is a deep need to understand the immunometabolic bases of the main etiological factors of T2D that affect the severity of COVID-19. Here, we discuss how hyperglycemia contributes to the cytokine storm commonly associated with COVID-19 by stimulating monocytes and macrophages to produce interleukin IL-1β, IL-6, and TNF-α in the airway epithelium. The main mechanisms through which hyperglycemia promotes reactive oxygen species release, inhibition of T cell activation, and neutrophil extracellular traps in the lungs of patients with severe SARS-CoV-2 infection are also studied. We further examine the molecular mechanisms by which proinflammatory cytokines induce insulin resistance, and their deleterious effects on pancreatic β-cell exhaustion in T2D patients critically ill with COVID-19. We address the effect of excess glucose on advanced glycation end product (AGE) formation and the role of AGEs in perpetuating pneumonia and acute respiratory distress syndrome. Finally, we discuss the contribution of preexisting endothelial dysfunction secondary to diabetes in the development of neutrophil trafficking, vascular leaking, and thrombotic events in patients with severe SARS-CoV-2 infection. As we outline here, T2D acts in synergy with SARS-CoV-2 infection to increase the progression, severity, and mortality of COVID-19. We think a better understanding of the T2D-related immunometabolic factors that contribute to exacerbate the severity of COVID-19 will improve our ability to identify patients with high mortality risk and prevent adverse outcomes.

• COVID-19
• SARS-CoV-2
• Type 2 diabetes
• Inflammation
• Hyperglycemia
• Prothrombotic state

• nanofibers
• peptide amphiphiles
• pulmonary hypertension
• targeted drug delivery

• Animals
• Hypertension, Pulmonary/drug therapy
• Lung
• Mice
• Nanofibers
• Receptor for Advanced Glycation End Products
• Tissue Distribution

• P30 CA016086 NCI NIH HHS
• R01 HL116577 NHLBI NIH HHS
• T32 GM086330 NIGMS NIH HHS

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.

Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).

Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).

This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.

Early screening for pulmonary arterial hypertension in patients with systemic sclerosis improves patient outcome. This study identified a novel eight-protein biomarker panel that has the potential to assist early detection of PAH in this patient group.https://bit.ly/373BNkL

• COVID-19
• SARS-CoV
• SARS-CoV-2
• pulmonary arterial hypertension
• transcriptomic profiling

• Algorithms
• Biomarkers/metabolism
• COVID-19/complications
• COVID-19/metabolism
• COVID-19/virology
• Gene Ontology
• Humans
• Hypertension, Pulmonary/complications
• Hypertension, Pulmonary/metabolism
• Information Storage and Retrieval
• MicroRNAs/metabolism
• Phylogeny
• Protein Interaction Maps
• SARS-CoV-2/isolation & purification
• Transcription Factors/metabolism

• National Science, Technology and Innovation Plan
• King Abdul-Aziz City for Science and Technology

• S100A8/A9
• biomarker
• calgranulin
• calprotectin
• lung

• Animals
• Humans
• Leukocyte L1 Antigen Complex/metabolism
• Lung Diseases/metabolism
• Lung Diseases/physiopathology

• 25(OH)D
• CDH
• Pulmonary hypertension
• Vascular remodeling

• Aptamer
• Pulmonary artery smooth muscle cells
• Receptor for advanced glycation end products

• RAGE
• S100A8/A9
• biologics
• fibrosis
• inflammation
• lung

• apoptosis
• hypertension, pulmonary
• hypoxia
• necrosis
• phenotype

• ESI-MS2
• actin
• bromine
• discovery
• halogen
• proteomics
• systems biology
• vascular permeability

• Animals
• Bromine/toxicity
• Cadherins/metabolism
• Capillary Permeability/drug effects
• Capillary Permeability/physiology
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Humans
• Lung/drug effects
• Lung/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Microvessels/drug effects
• Microvessels/metabolism
• Proteome/drug effects
• Proteome/metabolism

• 5UO1 ES027697 02 HHS | NIH | National Institute of Environmental Health Sciences (NIEHS)
• U01 ES026458 NIEHS NIH HHS
• 5UO1 ES026458 03 HHS | National Institutes of Health (NIH)
• T32 HL129948 NHLBI NIH HHS
• 3UO1 ES026458 03S1 HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
• P30CA013148 HHS | NIH | National Cancer Institute (NCI)
• U01 ES033265 NIEHS NIH HHS
• R01 DA049657 NIDA NIH HHS
• T32HL129948 HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)
• U01 ES027697 NIEHS NIH HHS
• P30 CA013148 NCI NIH HHS

• Angiotensin II/physiology
• Angiotensin-Converting Enzyme 2
• Betacoronavirus
• COVID-19
• Coronavirus Infections/complications
• Humans
• Pandemics
• Peptidyl-Dipeptidase A/physiology
• Pneumonia/etiology
• Pneumonia, Viral/complications
• Receptor for Advanced Glycation End Products/physiology
• Receptor, Angiotensin, Type 1/physiology
• SARS-CoV-2

• Ca2+ signaling
• pulmonary hypertension
• signaling
• whole exome sequencing

Vascular changes occur early in the development of obstructive airways disease. However, the vascular remodeling and dysfunction due to World Trade Center-Particulate Matter (WTC-PM) exposure are not well described and are therefore the focus of this investigation. C57Bl/6 female mice oropharyngeally aspirated 200 µg of WTC-PM₅₃ or phosphate-buffered saline (PBS) (controls). 24-hours (24-hrs) and 1-Month (1-M) after exposure, echocardiography, micro-positron emission tomography(µ-PET), collagen quantification, lung metabolomics, assessment of antioxidant potential and soluble-receptor for advanced glycation end products (sRAGE) in bronchoalveolar lavage(BAL) and plasma were performed. 24-hrs post-exposure, there was a significant reduction in (1) Pulmonary artery(PA) flow-velocity and pulmonary ejection time(PET) (2) Pulmonary acceleration time(PAT) and PAT/PET, while (3) Aortic ejection time(AET) and velocity time integral(VTI) were increased, and (4) Aortic acceleration time (AAT)/AET, cardiac output and stroke volume were decreased compared to controls. 1-M post-exposure, there was also significant reduction of right ventricular diameter as right ventricle free wall thickness was increased and an increase in tricuspid E, A peaks and an elevated E/A. The pulmonary and cardiac standard uptake value and volume 1-M post-exposure was significantly elevated after PM-exposure. Similarly, α-smooth muscle actin(α-SMA) expression, aortic collagen deposition was elevated 1-M after PM exposure. In assessment of the metabolome, prominent subpathways included advanced glycation end products (AGEs), phosphatidylcholines, sphingolipids, saturated/unsaturated fatty acids, eicosanoids, and phospholipids. BAL superoxide dismutase(SOD), plasma total-antioxidant capacity activity, and sRAGE (BAL and plasma) were elevated after 24-hrs. PM exposure and associated vascular disease are a global health burden. Our study shows persistent WTC-Cardiorespiratory and Vascular Dysfunction (WTC-CaRVD), inflammatory changes and attenuation of antioxidant potential after PM exposure. Early detection of vascular disease is crucial to preventing cardiovascular deaths and future work will focus on further identification of bioactive therapeutic targets.

There are three critical pathways for the pathogenesis and progression of pulmonary arterial hypertension (PAH): the prostacyclin (prostaglandin I₂) (PGI₂), nitric oxide (NO), and endothelin pathways. The current approved drugs targeting these three pathways, including prostacyclin (PGI₂), phosphodiesterase type-5 (PDE5) inhibitors, and endothelin receptor antagonists (ERAs), have been shown to be effective, however, PAH remains a severe clinical condition and the long-term survival of patients with PAH is still suboptimal. The full therapeutic abilities of available drugs are reduced by medication, patient non-compliance, and side effects. Nanoparticles are expected to address these problems by providing a novel drug delivery approach for the treatment of PAH. Drug-loaded nanoparticles for local delivery can optimize the efficacy and minimize the adverse effects of drugs. Prostacyclin (PGI₂) analogue, PDE5 inhibitors, ERA, pitavastatin, imatinib, rapamycin, fasudil, and oligonucleotides-loaded nanoparticles have been reported to be effective in animal PAH models and in vitro studies. However, the efficacy and safety of nanoparticle mediated-drug delivery systems for PAH treatment in humans are unknown and further clinical studies are required to clarify these points.

• endothelin
• nitric oxide
• prostaglandin I2
• pulmonary arterial hypertension

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/therapeutic use
• Animals
• Cyclic Nucleotide Phosphodiesterases, Type 5/genetics
• Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism
• Drug Delivery Systems/methods
• Humans
• Imatinib Mesylate/therapeutic use
• Nanoparticles/chemistry
• Pulmonary Arterial Hypertension/drug therapy
• Quinolines/therapeutic use

Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction.

In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism.

We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected.

Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture.

Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.

• Cilostazol
• Diabetes
• RAGE
• Vascular smooth muscle

• advanced glycation end products
• cell receptor for AGE
• pathogenesis
• pulmonary hypertension
• soluble RAGE
• therapeutic targets