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Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR.Circulation Research Feb 2024Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting...
BACKGROUND
Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure.
METHODS
Here, we show that direct targeting of the endothelium to uncouple eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice.
RESULTS
Critical phenotypic features include progressive elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricle (RV)/left ventricle plus septum (LV+S) weight ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; markedly increased total and mitochondrial superoxide production, substantially reduced tetrahydrobiopterin and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions. Intriguingly, novel in-house generated endothelial-specific dihydrofolate reductase (DHFR) transgenic mice (tg-EC-DHFR) were completely protected from the pathophysiological and molecular features of PH upon DAHP treatment or hypoxia exposure. Furthermore, DHFR overexpression with a pCMV-DHFR plasmid transfection in mice after initiation of DAHP treatment completely reversed PH phenotypes. DHFR knockout mice spontaneously developed PH at baseline and had no additional deterioration in response to hypoxia, indicating an intrinsic role of DHFR deficiency in causing PH. RNA-sequencing experiments indicated great similarity in gene regulation profiles between the DAHP model and human patients with PH.
CONCLUSIONS
Taken together, these results establish a novel human-like murine model of PH that has long been lacking in the field, which can be broadly used for future mechanistic and translational studies. These data also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH.
Topics: Animals; Humans; Mice; Endothelium; Hypertension, Pulmonary; Hypoxia; Mice, Knockout; Mice, Transgenic; Nitric Oxide Synthase Type III; Tetrahydrofolate Dehydrogenase; Hypoxanthines; Disease Models, Animal
PubMed: 38299369
DOI: 10.1161/CIRCRESAHA.123.323090 -
Cells May 2024Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing... (Review)
Review
Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing and remodeling extracellular matrixes and organizing functional tissue networks, which are essential for tissue homeostasis and various human diseases. Pulmonary hypertension (PH) is a devastating syndrome with high mortality, characterized by remodeling of the pulmonary vasculature and significant cellular and structural changes within the intima, media, and adventitia layers. Most research on PH has focused on alterations in the intima (endothelial cells) and media (smooth muscle cells). However, research over the past decade has provided strong evidence of the critical role played by pulmonary artery adventitial fibroblasts in PH. These fibroblasts exhibit the earliest, most dramatic, and most sustained proliferative, apoptosis-resistant, and inflammatory responses to vascular stress. This review examines the aberrant phenotypes of PH fibroblasts and their role in the pathogenesis of PH, discusses potential molecular signaling pathways underlying these activated phenotypes, and highlights areas of research that merit further study to identify promising targets for the prevention and treatment of PH.
Topics: Humans; Hypertension, Pulmonary; Fibroblasts; Animals; Signal Transduction; Pulmonary Artery
PubMed: 38891046
DOI: 10.3390/cells13110914 -
CircALMS1 Alleviates Pulmonary Microvascular Endothelial Cell Dysfunction in Pulmonary Hypertension.Journal of the American Heart... Mar 2024Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains...
BACKGROUND
Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains undefined. Thus, we aimed to identify specifically expressed circular RNAs in pulmonary microvascular endothelial cells (PMECs) under hypoxia and PH.
METHODS AND RESULTS
Deep RNA sequencing and quantitative real-time polymerase chain reaction revealed that circALMS1 (circular RNA Alstrom syndrome protein 1) was reduced in human PMECs under hypoxia (<0.0001). Molecular biology and histopathology experiments were used to elucidate the roles of circALMS1 in regulating PMEC dysfunction among patients with PH. The circALMS1 expression was decreased in the plasma of patients with PH (=0.0315). Patients with lower circALMS1 levels had higher risk of death (=0.0006). Moreover, the circALMS1 overexpression of adeno-associated viruses improved right ventricular function and reduced pulmonary vascular remodeling in monocrotaline-PH and sugen/hypoxia-PH rats (<0.05). Furthermore, circALMS1 overexpression promoted apoptosis and inhibited PMEC proliferation and migration under hypoxia by directly downregulating miR-17-3p (<0.05). Dual luciferase assay confirmed the direct binding of circALMS1 to miR-17-3p and miR-17-3p binding to its target gene YT521-B homology domain-containing family protein 2 (YTHDF2) (<0.05). The YTHDF2 levels were also downregulated in hypoxic PMECs (<0.01). The small interfering RNA YTHDF2 reversed the effects of miR-17-3p inhibitors on PMEC proliferation, migration, and apoptosis. Finally, the results indicated that, although YTHDF2, as an N(6)-methyladenosine reader protein, contributes to the degradation of many circular RNAs, it could not regulate the circALMS1 levels in PMECs (=0.9721).
CONCLUSIONS
Our study sheds new light on circALMS1-regulated dysfunction of PMECs by the miR-17-3p/YTHDF2 pathway under hypoxia and provides insights into the underlying pathogenesis of PH.
Topics: Humans; Rats; Animals; Hypertension, Pulmonary; MicroRNAs; Endothelial Cells; RNA, Circular; Pulmonary Artery; Hypoxia; Cell Proliferation
PubMed: 38497483
DOI: 10.1161/JAHA.123.031867 -
Immunity, Inflammation and Disease Nov 2023Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but... (Review)
Review
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but it is thought to involve a combination of genetic and environmental factors. There is no cure for IPF, and treatment is focused on slowing disease progression and relieving symptoms.
AIMS
We aimed in this review to investigate and provide the latest insights into IPF management modalities, including the potential of Saracatinibas a substitute for current IPF drugs. We also investigated the therapeutic potential of Sotatercept in addressing pulmonary hypertension associated with IPF.
MATERIALS AND METHODS
We conducted a comprehensive literature review of relevant studies on IPF management. We searched electronic databases, including PubMed, Scopus, Embase, and Web of science.
RESULTS
The two Food and Drug Administration-approved drugs for IPF, Pirfenidone, and Nintedanib, have been pivotal in slowing disease progression, yet experimental evidence suggests that Saracatinib surpasses their efficacy. Preclinical trials investigating the potential of Saracatinib, a tyrosine kinase inhibitor, have shown to be more effective than current IPF drugs in slowing disease progression in preclinical studies. Also, Sotatercept,a fusion protein, has been shown to reduce pulmonary vascular resistance and improve exercise tolerance in patients with PH associated with IPF in clinical trials.
CONCLUSIONS
The advancements discussed in this review hold the promise of improving the quality of life for IPF patients and enhancing our understanding of this condition. There remains a need for further research to confirm the efficacy and safety of new IPF treatments and to develop more effective strategies for managing exacerbations.
Topics: United States; Humans; Hypertension, Pulmonary; Quality of Life; Idiopathic Pulmonary Fibrosis; Disease Progression
PubMed: 38018591
DOI: 10.1002/iid3.1079 -
BMC Pulmonary Medicine Jul 2023The role of echocardiography in the diagnostic and prognostic assessment of pulmonary hypertension (PH) has been widely studied recently. However, these findings have... (Review)
Review
BACKGROUND
The role of echocardiography in the diagnostic and prognostic assessment of pulmonary hypertension (PH) has been widely studied recently. However, these findings have not undergone normative evaluation and may provide confusing evidence for clinicians. To evaluate and summarize existing evidence, we performed an umbrella review.
METHODS
Systematic reviews and meta-analyses were searched in PubMed, Embase, Web of Science, and Cochrane Library from inception to September 4, 2022. The methodological quality of the included studies was assessed using Assessment of Multiple Systematic Reviews (AMSTAR), and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the quality of evidence.
RESULTS
Thirteen meta-analyses (nine diagnostic and four prognostic studies) were included after searching four databases. The methodological quality of the included studies was rated as high (62%) or moderate (38%) by AMSTAR. The thirteen included meta-analyses involved a total of 28 outcome measures. The quality of evidence for these outcomes were high (7%), moderate (29%), low (39%), and very low (25%) using GRADE methodology. In the detection of PH, the sensitivity of systolic pulmonary arterial pressure is 0.85-0.88, and the sensitivity and specificity of right ventricular outflow tract acceleration time are 0.84. Pericardial effusion, right atrial area, and tricuspid annulus systolic displacement provide prognostic value in patients with pulmonary arterial hypertension with hazard ratios between 1.45 and 1.70. Meanwhile, right ventricular longitudinal strain has independent prognostic value in patients with PH, with a hazard ratio of 2.96-3.67.
CONCLUSION
The umbrella review recommends echocardiography for PH detection and prognosis. Systolic pulmonary arterial pressure and right ventricular outflow tract acceleration time can be utilized for detection, while several factors including pericardial effusion, right atrial area, tricuspid annular systolic displacement, and right ventricular longitudinal strain have demonstrated prognostic significance.
TRIAL REGISTRATION
PROSPERO (CRD42022356091), https://www.crd.york.ac.uk/prospero/ .
Topics: Humans; Atrial Fibrillation; Echocardiography; Hypertension, Pulmonary; Pericardial Effusion; Prognosis; Systematic Reviews as Topic; Meta-Analysis as Topic
PubMed: 37430308
DOI: 10.1186/s12890-023-02552-y -
Respiratory Research Nov 2023Interstitial lung disease (ILD) and pulmonary hypertension (PH) represent the major causes of mortality in systemic sclerosis (SSc). Patients with systemic sclerosis and...
BACKGROUND
Interstitial lung disease (ILD) and pulmonary hypertension (PH) represent the major causes of mortality in systemic sclerosis (SSc). Patients with systemic sclerosis and combined PH and ILD (SSc-PH-ILD) generally have a poor prognosis. Predictors of survival and of potential benefit of treatment are lacking in patients with SSc-PH-ILD.
OBJECTIVE
To identify specific plasma protein expression patterns associated with survival in patients with SSc-PH-ILD.
MATERIALS AND METHODS
Post-hoc analysis of a prospective multicenter French study in patients with PH-ILD. An untargeted proteomic analysis using mass spectrometry was performed to identify plasma protein changes associated with long-term overall survival in patients with SSc-PH-ILD.
RESULTS
Thirty two patients were included in the analysis, of whom 13 died during follow-up (median survival: 76.5 months). At baseline, survivors had less severe hemodynamic impairment [pulmonary vascular resistance of 4.4 Wood Units (IQR 3-5.2) vs. 6.2 Wood Units (IQR 4.2-10.7)] and higher carbon monoxide diffusing capacity [median 39% (IQR 35-44%) vs. 25% (IQR 22-30.5%)], than the 13 patients who died. Seven proteins, associated with haemostasis and fibrosis, were differentially expressed according to patients' survival. In the survivor group, two proteins were increased (ADAMTS13, SERPIND1) and five were decreased (PTGDS, OLFM1, C7, IGFBP7, FBN1) compared to the non-survivor groups.
CONCLUSION
The prognosis of SSc-PH-ILD patients is poor. This proteomic approach found 7 plasma proteins (involved in haemostasis and fibrosis pathways) associated with survival. These potential biomarkers may be good candidates to prognostic enrichment.
Topics: Humans; Hypertension, Pulmonary; Prospective Studies; Proteomics; Scleroderma, Systemic; Lung Diseases, Interstitial; Biomarkers; Pulmonary Arterial Hypertension; Fibrosis; Blood Proteins; Lung
PubMed: 37936223
DOI: 10.1186/s12931-023-02578-0 -
Respiratory Research Aug 2023Up-regulation of ceramides in pulmonary hypertension (PH), contributing to perturbations in sphingolipid homeostasis and the transition of cells to a senescence state....
BACKGROUND
Up-regulation of ceramides in pulmonary hypertension (PH), contributing to perturbations in sphingolipid homeostasis and the transition of cells to a senescence state. We assessed the safety, feasibility, and efficiency of acid ceramidase gene transfer in a rodent PH model.
METHODS
A model of PH was established by the combination of left pneumonectomy and injection of Sugen toxin. Magnetic resonance imaging and right heart catheterization confirmed development of PH. Animals were subjected to intratracheal administration of synthetic adeno-associated viral vector (Anc80L65) carrying the acid ceramidase (Anc80L65.AC), an empty capsid vector, or saline. Therapeutic efficacy was evaluated 8 weeks after gene delivery.
RESULTS
Hemodynamic assessment 4 weeks after PH model the development demonstrated an increase in the mean pulmonary artery pressure to 30.4 ± 2.13 mmHg versus 10.4 ± 1.65 mmHg in sham (p < 0.001), which was consistent with the definition of PH. We documented a significant increase in pulmonary vascular resistance in the saline-treated (6.79 ± 0.85 mm Hg) and empty capsid (6.94 ± 0.47 mm Hg) groups, but not in animals receiving Anc80L65.AC (4.44 ± 0.71 mm Hg, p < 0.001). Morphometric analysis demonstrated an increase in medial wall thickness in control groups in comparison to those treated with acid ceramidase. After acid ceramidase gene delivery, a significant decrease of pro-inflammatory factors, interleukins, and senescence markers was observed.
CONCLUSION
Gene delivery of acid ceramidase provided tropism to pulmonary tissue and ameliorated vascular remodeling with right ventricular dysfunction in pulmonary hypertension.
Topics: Animals; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Acid Ceramidase; Familial Primary Pulmonary Hypertension; Genetic Therapy; Pulmonary Artery; Ventricular Dysfunction, Right
PubMed: 37568148
DOI: 10.1186/s12931-023-02487-2 -
Pulmonology Dec 2023Patients with pulmonary arterial hypertension (PAH) require risk assessments for prognosis and appropriate therapy. These assessments need to be improved by... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
Patients with pulmonary arterial hypertension (PAH) require risk assessments for prognosis and appropriate therapy. These assessments need to be improved by incorporating clinical and laboratory data such as the analysis of the right ventricle. We aim to establish echocardiographic morphometric data of the right ventricle and its relationship with the left ventricle, to estimate the hemodynamic severity of precapillary pulmonary hypertension (PHprecapillary).
METHODS
This cohort, prospective, observational, and cross-sectional study included 41 consecutive patients with PHprecapillary using echocardiographic study and cardiac catheterization.
RESULTS
Patients' mean age was 44.0±16.4 years, and 37 were women (90.2%). Idiopathic PAH was diagnosed in 18 patients (43.9%). The World Health Organization/New York Association functional class was III or IV in 31 patients (75.6%). The ratio of the right to left ventricles (RV/LV) echocardiographic diastolic diameters was associated with pulmonary arterial pressures in cardiac catheterization, with the best cutoff per receiver operating characteristic curve being 0.8 for systolic pressure (sensitivity 90.0%, specificity 78.3%, area under the curve [AUC] 0.882) and mean pressure (sensitivity 60.0%, specificity 95.7%, AUC 0.823). Spearman's correlation (R) of RV/LV echocardiographic ratio and the hemodynamic variables was significant for systolic pressure (R = 0.7015, p < 0.0001), mean pressure (R = 0.6332, p < 0.0001), transpulmonary pressure gradient (R = 0.6524, p < 0.0001), pulmonary vascular resistance (R = 0.6076, p = 0.0021), and pulmonary vascular resistance index (R = 0.6229, p = 0.0014).
CONCLUSION
The ratio of RV/LV echocardiographic diastolic diameters contribute to the estimates the hemodynamic severity of precapillary pulmonary hypertension. The best cutoff for this assessment was RV/LV of 0.8.
Topics: Humans; Female; Adult; Middle Aged; Male; Hypertension, Pulmonary; Prospective Studies; Cross-Sectional Studies; Echocardiography; Hemodynamics
PubMed: 34969648
DOI: 10.1016/j.pulmoe.2021.11.007 -
Journal of Cardiac Failure Sep 2023Right heart failure (RHF) is associated with a dismal prognosis in patients with pulmonary hypertension (PH). Exercise right heart catheterization may unmask right heart...
BACKGROUND
Right heart failure (RHF) is associated with a dismal prognosis in patients with pulmonary hypertension (PH). Exercise right heart catheterization may unmask right heart maladaptation as a sign of RHF. We sought to (1) define the normal limits of right atrial pressure (RAP) increase during exercise; (2) describe the right heart adaptation to exercise in PH owing to heart failure with preserved ejection fraction (PH-HFpEF) and in pulmonary arterial hypertension (PAH); and (3) identify the factors associated with right heart maladaptation during exercise.
METHODS AND RESULTS
We analyzed rest and exercise right heart catheterization from patients with PH-HFpEF and PAH. Right heart adaptation was described by absolute or cardiac output (CO)-normalized changes of RAP during exercise. Individuals with noncardiac dyspnea (NCD) served to define abnormal RAP responses (>97.5th percentile). Thirty patients with PH-HFpEF, 30 patients with PAH, and 21 patients with NCD were included. PH-HFpEF were older than PAH, with more cardiovascular comorbidities, and a higher prevalence of severe tricuspid regurgitation (P < .05). The upper limit of normal for peak RAP and RAP/CO slope in NCD were >12 mm Hg and ≥1.30 mm Hg/L/min, respectively. PH-HFpEF had higher peak RAP and RAP/CO slope than PAH (20 mm Hg [16-24 mm Hg] vs 12 mm Hg [9-19 mm Hg] and 3.47 mm Hg/L/min [2.02-6.19 mm Hg/L/min] vs 1.90 mm Hg/L/min [1.01-4.29 mm Hg/L/min], P < .05). A higher proportion of PH-HFpEF had RAP/CO slope and peak RAP above normal (P < .001). Estimated stressed blood volume at peak exercise was higher in PH-HFpEF than PAH (P < .05). In the whole PH cohort, the RAP/CO slope was associated with age, the rate of increase in estimated stressed blood volume during exercise, severe tricuspid regurgitation, and right atrial dilation.
CONCLUSIONS
Patients with PH-HFpEF display a steeper increase of RAP during exercise than those with PAH. Preload-mediated mechanisms may play a role in the development of exercise-induced RHF.
Topics: Humans; Hypertension, Pulmonary; Stroke Volume; Heart Failure; Tricuspid Valve Insufficiency; Noncommunicable Diseases; Hemodynamics; Cardiac Catheterization; Dyspnea; Exercise Test; Exercise Tolerance
PubMed: 37150503
DOI: 10.1016/j.cardfail.2023.04.009 -
Pneumologie (Stuttgart, Germany) Nov 2023In the recent ESC/ERS guidelines on the diagnosis and management of pulmonary hypertension (PH) several important changes have been made in respect of the definition and...
In the recent ESC/ERS guidelines on the diagnosis and management of pulmonary hypertension (PH) several important changes have been made in respect of the definition and classification of PH.The mPAP cut-off for defining PH was lowered. PH is now defined by an mPAP > 20 mmHg assessed by right heart catheterization. Moreover, the PVR threshold for defining precapillary PH was lowered. Precapillary PH is now defined by a PVR > 2 WU and a pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg. Furthermore, the increasing evidence for the clinical relevance of pulmonary exercise hemodynamics led to the reintroduction of exercise pulmonary hypertension (EPH) 1. EPH is characterized by a mPAP/CO-slope > 3 mmHg/L/min during exercise testing. In the classification of PH five groups are distinguished: Pulmonary arterial hypertension (group 1), PH associated with left heart disease (group 2), PH associated with lung diseases and/or hypoxia (Group 3), PH associated with pulmonary artery obstructions (group 4) and PH with unclear and/or multi-factorial mechanisms (group 5).In the following guideline-translation we focus on novel aspects regarding the definition and classification of PH and to provide additional background information.
Topics: Humans; Hypertension, Pulmonary; Hemodynamics; Heart Diseases; Cardiac Catheterization; Pulmonary Artery
PubMed: 37963475
DOI: 10.1055/a-2145-4648