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Scientific Reports Dec 2023Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene...
Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This "cell biopsy" method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Artery; Endothelial Cells; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Vascular Diseases; Wnt Signaling Pathway
PubMed: 38110438
DOI: 10.1038/s41598-023-48077-6 -
Frontiers in Immunology 2023Pulmonary fibrosis (PF) and pulmonary hypertension (PH) have common pathophysiological features, such as the significant remodeling of pulmonary parenchyma and vascular...
Pulmonary fibrosis (PF) and pulmonary hypertension (PH) have common pathophysiological features, such as the significant remodeling of pulmonary parenchyma and vascular wall. There is no effective specific drug in clinical treatment for these two diseases, resulting in a worse prognosis and higher mortality. This study aimed to screen the common key genes and immune characteristics of PF and PH by means of bioinformatics to find new common therapeutic targets. Expression profiles are downloaded from the Gene Expression Database. Weighted gene co-expression network analysis is used to identify the co-expression modules related to PF and PH. We used the ClueGO software to enrich and analyze the common genes in PF and PH and obtained the protein-protein interaction (PPI) network. Then, the differential genes were screened out in another cohort of PF and PH, and the shared genes were crossed. Finally, RT-PCR verification and immune infiltration analysis were performed on the intersection genes. In the result, the positive correlation module with the highest correlation between PF and PH was determined, and it was found that lymphocyte activation is a common feature of the pathophysiology of PF and PH. Eight common characteristic genes ( and ) were gained. Immune infiltration showed that compared with the control group, resting CD4 memory T cells were upregulated in PF and PH. Combining the results of crossing characteristic genes in ImmPort database and RT-PCR, the important gene was obtained. Knocking down could significantly reduce the proliferation and apoptosis resistance in pulmonary microvascular endothelial cells, pulmonary smooth muscle cells, and fibroblasts induced by hypoxia, platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-β1 (TGF-β1), respectively. Our work identified the common biomarkers of PF and PH and provided a new candidate gene for the potential therapeutic targets of PF and PH in the future.
Topics: Humans; Pulmonary Fibrosis; Hypertension, Pulmonary; Endothelial Cells; Genes, Regulator; Computational Biology; Proteins
PubMed: 37731513
DOI: 10.3389/fimmu.2023.1197752 -
Clinical and Experimental Hypertension... Dec 2023Pulmonary arterial hypertension (PAH) is a disease with a high mortality and few treatment options to prevent the development of pulmonary vessel remodeling, pulmonary...
Pulmonary arterial hypertension (PAH) is a disease with a high mortality and few treatment options to prevent the development of pulmonary vessel remodeling, pulmonary vascular resistance, and right ventricular failure. Canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is originally used in diabetes patients which could assist the glucose excretion and decrease blood glucose. Recently, a few studies have reported the protective effect of SGLT2 inhibitor on monocrotaline-induced PAH. However, the effects of canagliflozin on hypobaric hypoxia-induced PAH as well as its mechanism still unclear. In this study, we used hypobaric hypoxia-induced PAH mice model to demonstrate if canagliflozin could alleviate PAH and prevent pulmonary vessel remodeling. We found that daily canagliflozin administration significantly improved survival in mice with hypobaric hypoxia-induced PAH compared to vehicle control. Canagliflozin treatment significantly reduced right ventricular systolic pressure and increased pulmonary acceleration time determined by hemodynamic assessments. Canagliflozin significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles compared to vehicle treated mice. In addition, canagliflozin inhibited the proliferation and migration of pulmonary arterial smooth muscle cells through suppressing glycolysis and reactivating AMP-activated protein kinase signaling pathway under hypoxia condition. In summary, our findings suggest that canagliflozin is sufficient to inhibit pulmonary arterial remodeling which is a potential therapeutic strategy for PAH treatment.
Topics: Humans; Mice; Animals; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Canagliflozin; Pulmonary Artery; Hypoxia; Myocytes, Smooth Muscle; Cell Proliferation; Glucose; Vascular Remodeling; Monocrotaline
PubMed: 37970663
DOI: 10.1080/10641963.2023.2278205 -
Innere Medizin (Heidelberg, Germany) Jun 2024Heritable pulmonary arterial hypertension (PAH) can be triggered by at least 18 genes. The most frequently altered gene is the bone morphogenetic protein receptor 2... (Review)
Review
Heritable pulmonary arterial hypertension (PAH) can be triggered by at least 18 genes. The most frequently altered gene is the bone morphogenetic protein receptor 2 (BMPR2). Further genes from the same pathway are also well known PAH-causing genes. Genetic testing can aid to confirm differential diagnoses such as a pulmonary veno-occlusive disease. It also enables the testing of healthy family members. In addition to the PAH patient population particularly served by genetic testing, this article touches on the mode of inheritance and provides insights into the first treatments soon on the market that rebalance the BMPR2 signaling pathway.
Topics: Humans; Bone Morphogenetic Protein Receptors, Type II; Genetic Testing; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Genetic Predisposition to Disease; Signal Transduction
PubMed: 38771375
DOI: 10.1007/s00108-024-01718-y -
Frontiers in Endocrinology 2023Pulmonary arterial hypertension (PAH) is a vascular remodeling disease, characterized by increased blood pressure levels in pulmonary circulation, leading to a... (Review)
Review
Pulmonary arterial hypertension (PAH) is a vascular remodeling disease, characterized by increased blood pressure levels in pulmonary circulation, leading to a restriction in the circulation flow and heart failure. Although the emergence of new PAH therapies has increased survival rates, this disease still has a high mortality and patients that receive diagnosis die within a few years. The pathogenesis of PAH involves multiple pathways, with a complex interaction of local and distant cytokines, hormones, growth factors, and transcription factors, leading to an inflammation that changes the vascular anatomy in PAH patients. These abnormalities involve more than just the lungs, but also other organs, and between these affected organs there are different metabolic dysfunctions implied. Recently, several publications demonstrated in PAH patients a disturbance in glucose metabolism, demonstrated by higher levels of glucose, insulin, and lipids in those patients. It is possible that a common molecular mechanism can have a significant role in this connection. In this regard, this narrative review intends to focus on the recent papers that mainly discuss the molecular determinants between insulin resistance (IR) associated PAH, which included obesity subclinical inflammation induced IR, PPAR gamma and Adiponectin, BMPR2, mitochondrial dysfunction and endoplasmic reticulum stress. Therefore, the following review will summarize some of the existing data for IR associated PAH, focusing on the better understanding of PAH molecular mechanisms, for the development of new translational therapies.
Topics: Humans; Hypertension, Pulmonary; Insulin Resistance; Lung; Inflammation
PubMed: 38239990
DOI: 10.3389/fendo.2023.1283233 -
Pulmonary Pharmacology & Therapeutics Dec 2023Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It... (Review)
Review
Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It is approved for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. Tyvaso DPI utilizes single-use prefilled cartridges to ensure proper dosing. Unlike nebulizer devices, administration of Tyvaso DPI is passive and does not require coordination with the device. The low-flow rate design results in targeted delivery to the peripheral lungs due to minimal drug loss from impaction in the oropharynx. The inert fumaryl diketopiperazine (FDKP) excipient forms microparticles that carry treprostinil into the airways, with a high fraction of the particles in the respirable range. In a clinical study in patients with pulmonary arterial hypertension, Tyvaso DPI had similar exposure and pharmacokinetics, low incidence of adverse events, and high patient satisfaction compared with nebulized treprostinil solution. Tyvaso DPI may be considered as a first prostacyclin agent or for those that do not tolerate other prostacyclin formulations, patients with pulmonary comorbidities, patients with mixed Group 1 and Group 3 pulmonary hypertension, or those that prefer an active lifestyle and need a portable, non-invasive treatment. Tyvaso DPI is a patient-preferred, maintenance-free, safe delivery option that may improve patient compliance and adherence.
Topics: Humans; Dry Powder Inhalers; Hypertension, Pulmonary; Pharmaceutical Preparations; Pulmonary Arterial Hypertension; Epoprostenol; Administration, Inhalation; Familial Primary Pulmonary Hypertension
PubMed: 37967762
DOI: 10.1016/j.pupt.2023.102266 -
Annals of Clinical and Translational... Oct 2023Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling with resultant abnormal increase in pulmonary artery pressure and...
Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling with resultant abnormal increase in pulmonary artery pressure and right heart dysfunction. There is evidence that PAH includes cognitive impairment. However, the cognitive impairment syndrome has not been well described, and both the underlying mechanism and the relationship between cardiopulmonary and cognitive dysfunction in PAH are unknown. We performed cognitive evaluations and same day sub-maximum cardiopulmonary exercise testing on adult subjects with PAH. A frontal-subcortical syndrome suggestive of vascular cognitive impairment was found in 26% of subjects and was associated with noninvasive markers of pulmonary vascular remodeling.
Topics: Adult; Humans; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Vascular Remodeling
PubMed: 37550957
DOI: 10.1002/acn3.51867 -
International Journal of Molecular... Oct 2023Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many... (Review)
Review
Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews studies that test interventions on pulmonary artery banding (PAB), a model of isolated RV disfunction, and PH models. Multiple tested drugs both improved pulmonary vascular hemodynamics in PH models and improved RV structure and function in PAB animals. PH models and PAB animals frequently exhibited similar results (73.1% concordance). Macitentan, sildenafil, and tadalafil improved most tested pathophysiological parameters in PH models, but almost none in PAB animals. Results are frequently not consistent with other studies, possibly due to the methodology, which greatly varied. Some research groups start treating the animals immediately, and others wait up to 4 weeks from model induction. Treatment duration and choice of anaesthetic are other important differences. This review shows that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans. However, a uniformization of methods may increase comparability between studies and, thus, improve translation to clinical trials.
Topics: Humans; Mice; Rats; Animals; Pulmonary Arterial Hypertension; Ventricular Function, Right; Pulmonary Artery; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Disease Models, Animal
PubMed: 37958522
DOI: 10.3390/ijms242115539 -
Nature Communications Nov 2023Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA...
Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm). Gene expression analysis of EC-Atm and EC-Bmpr2 lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2 mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.
Topics: Mice; Humans; Animals; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Pulmonary Artery; DNA Damage; Bone Morphogenetic Protein Receptors, Type II; Forkhead Transcription Factors
PubMed: 37989727
DOI: 10.1038/s41467-023-43039-y -
European Respiratory Review : An... Dec 2023Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and potentially life-threatening complication of acute pulmonary embolism. It is characterised by...
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and potentially life-threatening complication of acute pulmonary embolism. It is characterised by persistent fibro-thrombotic pulmonary vascular obstructions and elevated pulmonary artery pressure leading to right heart failure. The diagnosis is based on two steps, as follows: 1) suspicion based on symptoms, echocardiography and ventilation/perfusion scan and 2) confirmation with right heart catheterisation, computed tomography pulmonary angiography and, in most cases, digital subtraction angiography. The management of CTEPH requires a multimodal approach, involving medical therapy, interventional procedures and surgical intervention. This clinical-radiological-pathological correlation paper illustrates the diagnostic and therapeutic management of two patients. The first had chronic thromboembolic pulmonary disease without pulmonary hypertension at rest but with significant physical limitation and was successfully treated with pulmonary endarterectomy. The second patient had CTEPH associated with splenectomy and was considered unsuitable for surgery because of exclusive subsegmental lesions combined with severe pulmonary hypertension. The patient benefited from multimodal treatment involving medical therapy followed by multiple sessions of balloon pulmonary angioplasty. Both patients had normalised functional capacity and pulmonary haemodynamics 3-6 months after the interventional treatment. These two examples show that chronic thromboembolic pulmonary diseases are curable if diagnosed promptly and referred to CTEPH centres for specialist treatment.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Embolism; Angioplasty, Balloon; Angiography; Tomography, X-Ray Computed; Chronic Disease; Endarterectomy; Pulmonary Artery
PubMed: 38123236
DOI: 10.1183/16000617.0149-2023