Abstract-Dysregulated expression of bone morphogenetic protein receptor type II (BMPR2) is a pathogenetic hallmark of pulmonary hypertension. Downregulation of BMPR2 protein but not mRNA has been observed in multiple animal models mimicking the disease, indicating a posttranscriptional mechanism of regulation. Because microRNAs (miRNAs) regulate gene expression mainly through inhibition of target gene translation, we hypothesized that miRNAs may play a role in the modulation of BMPR2. Performing a computational algorithm on the BMPR2 gene, several miRNAs encoded by the miRNA cluster 17/92 (miR-17/92) were retrieved as potential regulators. Ectopic overexpression of miR-17/92 resulted in a strong reduction of the BMPR2 protein, and a reporter gene system showed that BMPR2 is directly targeted by miR-17-5p and miR-20a. By stimulation experiments, we found that the miR-17/92 cluster is modulated by interleukin (IL)-6, a cytokine involved in the pathogenesis of pulmonary hypertension. Because IL-6 signaling is mainly mediated by STAT3 (signal transducer and activator of transcription 3), the expression of STAT3 was knocked down by small interfering RNA, which abolished the IL-6 -mediated expression of miR-17/92. Consistent with these data, we found a highly conserved STAT3-binding site in the promoter region of the miR-17/92 gene (C13orf25). Promoter studies confirmed that IL-6 enhances transcription of C13orf25 through this distinct region. Finally, we showed that persistent activation of STAT3 leads to repressed protein expression of BMPR2. Taken together, we describe here a novel STAT3-miR-17/92-BMPR2 pathway, thus providing a mechanistic explanation for the loss of BMPR2 in the development of pulmonary hypertension. Key Words: pulmonary hypertension Ⅲ BMPR2 Ⅲ miR-17/92 Ⅲ interleukin-6 Ⅲ STAT3 P ulmonary hypertension is a devastating condition defined by the sustained elevation of pulmonary vascular resistance that leads rapidly to right heart failure and death when left untreated. 1 The pathogenesis of pulmonary hypertension is characterized by vascular remodeling and vasoconstriction. 2 Many chemotactic and inflammatory factors have been associated with these vascular changes including interleukin (IL)-6 and transforming growth factor (TGF). [3][4][5] In familial pulmonary arterial hypertension, germline mutations in the gene encoding the type II receptor of the bone morphogenetic protein (BMPR2) comprise a genetic hallmark of the disease. 6 BMPR2 is a surface protein receptor that belongs to the transforming growth factor (TGF) family. Its expression on endothelial and vascular smooth muscle cells mediates binding of bone morphogenetic proteins (BMPs) that have been identified as inhibitors of vascular smooth muscle cell proliferation while inducing cell death. 7 Thus, it was suggested that the downregulation of BMPR2 might lead to significant alterations in these signaling cascades and, ultimately, to remodeling of the pulmonary vascular bed. 8 Of interest, alterations in the surface expression of BMPR2 ha...
Both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE. Dexamethasone prophylaxis may also reduce the incidence of AMS in these adults. ClinicalTrials.gov identifier: NCT00274430.
BackgroundThe six-minute walk test (6MWT) is a simple, low tech, safe and well established, self-paced assessment tool to quantify functional exercise capacity in adults. The definition of normal 6MWT in children is especially demanding since not only parameters like height, weight and ethnical background influence the measurement, but may be as crucial as age and the developmental stage. The aim of this study is establishing reference values for the 6MWT in healthy children and adolescents in Switzerland and to investigate the influence of age, anthropometrics, heart rate, blood pressure and physical activity on the distance walked.MethodsChildren and adolescents between 5–17 years performed a 6MWT. Short questionnaire assessments about their health state and physical activities. anthropometrics and vitals were measured before and after a 6-minute walk test and were previously defined as secondary outcomes.ResultsAge, height, weight and the heart rate after the 6MWT all predicted the distance walked according to different regression models: age was the best single predictor and mostly influenced walk distance in younger age, anthropometrics were more important in adolescents and females. Heart rate after the 6MWT was an important distance predictor in addition to age and outreached anthropometrics in the majority of subgroups assessed.ConclusionsThe 6MWT in children and adolescents is feasible and practical. The 6MWT distance depends mainly on age; however, heart rate after the 6MWT, height and weight significantly add information and should be taken into account mainly in adolescents. Reference equations allow predicting 6-minute walk test distance and may help to better assess and compare outcomes in young patients with cardiovascular and respiratory diseases and are highly warranted for different populations.
In patients with severe sepsis or septic shock, BNP and N-terminal pro-BNP values are highly elevated and, despite significant hemodynamic differences, comparable with those found in acute HF patients. It remains to be determined how elevations of natriuretic peptide levels are linked to inflammation and sepsis-associated myocardial dysfunction.
Corticosteroids, but not phosphodiesterase-5 inhibition, partially prevented the limitation of exercise capacity in subjects with intense hypoxic pulmonary vasoconstriction at high altitude.
Background: Pulmonary hypertension (PH) impairs quality of life, exercise performance and survival. Simple measures to monitor the disease are needed. Objectives: We tested whether actigraphy by a wrist-worn device in the patient's home reflects disease severity in PH patients. Methods: Twenty-three outpatients with pulmonary arterial and chronic thromboembolic PH (15 females), functional classes II-IV, underwent clinical examination and actigraphy over 2 weeks while pursuing their usual life at home. Actigraphies were correlated with clinical data and mean pulmonary artery pressure (mPAP). Deaths, lung transplantations and pulmonary endarterectomy were recorded over 4 years. Results: Actigraphies revealed a mean ± SD daytime activity duration of 14:57 ± 1:14 h with 146 ± 125 activity counts/min. Very severely impaired patients (mPAP 50 ± 7 mm Hg) were inactive for longer periods at night (8:25 ± 1:18 h) and less active during the day (54 ± 44 counts/min) when compared to modestly impaired patients (mPAP 33 ± 7 mm Hg; inactive at night for 6:58 ± 0:39 h; daytime activity 229 ± 148 counts/min, p < 0.05 in all instances). Out of 19 patients followed for 4 years, 5 died and 1 received a lung transplantation. Kaplan-Meier analysis revealed a shorter survival without lung transplantation in patients with a duration of daytime activity of <15 h/day than those with >15 h/day duration (log rank, p = 0.026). Conclusion: A long nocturnal rest and reduced daytime activity recorded by actigraphy are associated with severe hemodynamic impairment and reduced survival in patients with PH. Therefore, wrist actigraphy performed during everyday life in the patient's home holds promise as a simple tool for the assessment of disease severity and prognosis in patients with PH.
BackgroundHomeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling.ObjectiveThis study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation.MethodsMicrobiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture.ResultsWe identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition.ConclusionsHost-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.