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Clinical and Experimental Pharmacology... Jul 2022Endothelin-1 (ET-1) is implicated in the development of atherosclerosis and mediates glycosaminoglycan (GAG) chain hyperelongation on proteoglycans. Our aim was to...
Endothelin-1 (ET-1) is implicated in the development of atherosclerosis and mediates glycosaminoglycan (GAG) chain hyperelongation on proteoglycans. Our aim was to identify the ET-1-mediated signalling pathway involving NADPH oxidase (NOX), p38 MAP kinsae and Smad2 linker region phosphorylation (phospho-Smad2L) regulate GAG synthesising enzymes mRNA expression (C4ST-1 and ChSy1) involved in GAG chains hyperelongation in human vascular smooth muscle cells (VSMCs). Signalling intermediates were detected and quantified by Western blotting and the mRNA levels of GAG synthesising enzymes were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). ET-1 treatment of human VSMCs resulted in an increase in phospho-Smad2L level. The TGF-β receptor antagonist, SB431542 and the mixed ET and ET receptor antagonist bosentan, inhibited ET-1-mediated phospho-Smad2L level. In the presence of apocynin and diphenyleneiodonium chloride (DPI) (NOX inhibitors) and SB239063 (p38 inhibitor) ET-1-mediated phospho-Smad2L levels were inhibited. The gene expression levels of GAG synthesising enzymes post-ET-1 treatment were increased compared to untreated controls (p < 0.01). The ET-mediated the mRNA levels of these enzymes were blocked by the bosentan, SB431542, SB239063, DPI, apocynin and antioxidant N-acetyl-L-cysteine (NAC). ET-1-mediated signalling to GAG synthesising enzymes gene expression occurs via transactivation-dependent pathway involving NOX, p38 MAP kinsae and Smad2 linker region phosphorylation.
Topics: Bosentan; Endothelin-1; Genes, gag; Glycosaminoglycans; Humans; NADPH Oxidases; Phosphorylation; RNA, Messenger
PubMed: 35527471
DOI: 10.1111/1440-1681.13650 -
Cardiology in Review 2010Pulmonary arterial hypertension (PAH) is an entity that is known to complicate connective tissue diseases (CTD). PAH in CTD is a very important diagnosis which greatly... (Review)
Review
Pulmonary arterial hypertension (PAH) is an entity that is known to complicate connective tissue diseases (CTD). PAH in CTD is a very important diagnosis which greatly affects treatment and prognosis. The most commonly affected CTD is scleroderma, although lupus, inflammatory myopathies such as poly and dermatomyositis, and mixed CTD are also associated with PAH. The manifestations of PAH have both similarities and differences when occurring in the setting of CTD as compared with idiopathic PAH. These differences are most notable in scleroderma. In this section we will discuss the features of PAH as they appear in CTDs, and in particular, scleroderma. The focus of this article is an approach to the diagnosis and treatment of PAH in CTD, and how this setting might differ from idiopathic and other forms of PAH.
Topics: Antihypertensive Agents; Bosentan; Connective Tissue Diseases; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prognosis; Pyridazines; Scleroderma, Systemic; Sulfonamides
PubMed: 20160534
DOI: 10.1097/CRD.0b013e3181cbcde7 -
JACC. Heart Failure May 2017The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with... (Review)
Review
Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials.
OBJECTIVES
The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure.
BACKGROUND
Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking.
METHODS
In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure.
RESULTS
Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure.
CONCLUSIONS
Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.
Topics: Aged; Australia; Bosentan; Cause of Death; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Endothelin Receptor Antagonists; Europe; Female; Heart Failure; Humans; Internationality; Kaplan-Meier Estimate; Male; Middle Aged; Morbidity; North America; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Sulfonamides; Survival Analysis; Time Factors; Treatment Outcome
PubMed: 28449795
DOI: 10.1016/j.jchf.2017.02.021 -
Journal of the American Heart... Jul 2018
Topics: Bosentan; Cardiac Surgical Procedures; Disease Management; Endothelin Receptor Antagonists; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Vascular Malformations
PubMed: 29973393
DOI: 10.1161/JAHA.118.008587 -
Life Sciences Oct 2012The demonstration that endothelin production is upregulated in pulmonary artery hypertension (PAH) served as the rationale for developing endothelin-receptor antagonists... (Review)
Review
AIMS
The demonstration that endothelin production is upregulated in pulmonary artery hypertension (PAH) served as the rationale for developing endothelin-receptor antagonists (ERAs) as a treatment for PAH. This article reviews the primary studies demonstrating efficacy of ERAs in PAH.
MAIN METHODS
Multicenter, placebo-controlled trials and open-label extension studies.
KEY FINDINGS
Two orally active ERAs are currently approved for the treatment of PAH - the dual receptor antagonist bosentan, and the more selective ET(A) receptor antagonist ambrisentan-based on multicenter randomized clinical trials demonstrating efficacy and safety. Long-term experience with both agents supports maintenance of therapeutic effects in most patients. Adverse effects, including altered liver function and edema may occur and require careful monitoring.
SIGNIFICANCE
Despite failure to demonstrate efficacy of ERAs in other cardiopulmonary conditions, ERAs have a major role in the treatment algorithm for PAH.
Topics: Administration, Oral; Animals; Antihypertensive Agents; Bosentan; Drug Design; Drug Monitoring; Endothelin Receptor Antagonists; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sulfonamides
PubMed: 22884806
DOI: 10.1016/j.lfs.2012.07.033 -
Medicine Mar 2018Oral bosentan has been widely applied in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). A systemic review and meta-analysis was... (Meta-Analysis)
Meta-Analysis Review
The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease: A systematic review and meta-analysis.
BACKGROUND
Oral bosentan has been widely applied in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). A systemic review and meta-analysis was conducted for a therapeutic evaluation of oral bosentan in both adult and pediatric patients with PAH-CHD. The acute responses and a long-term effect were respectively assessed in a comparison with baseline characteristics, and the improvement of exercise tolerance was analyzed.
METHODS
PubMed, Medline, Embase, and Cochrane Central Register of clinical controlled trails or observational studies have been searched for a recording of bosentan effects on the PAH-CHD participants. For mortality and rate of adverse events (AEs), it was described in detail. Randomized-effects model or fixed-effects model was used to calculate different effective values with a sensitivity analysis.
RESULTS
Seventeen studies were pooled in this review, and 3 studies enrolled the pediatric patients. Among all studies, 456 patients were diagnosed with PAH-CHD, and 91.7% were treated with oral bosentan. With a term less than 6 months of bosentan therapy, there existed a significant improvement in 6-minute walk distance (6MWD) and the World Health Organization functional class (WHO-FC), but no such differences in Borg dyspnea index scores (BDIs) and the resting oxygen saturation (SpO2). Although with a prolonged treatment, not only 6MWD and FC, but also the resting SpO2 and heart rate were changed for a better exercise capability. Additionally, compared with the basic cardiopulmonary hemodynamics, it showed a statistically significant difference in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRi). Although a limitation of pooled studies with comparative outcomes of different terms, outcomes presented a lower WHO-FC which contributes to a success in a prolonged treatment.
CONCLUSIONS
Bosentan in PAH-CHD is well established and still requires clinical trials for an identification of its efficiency on CHD patients for an optimized period lessening a serious complication and the common AEs.
Topics: Adolescent; Adult; Bosentan; Child; Child, Preschool; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Humans; Infant; Middle Aged; Sulfonamides; Treatment Outcome; Young Adult
PubMed: 29517668
DOI: 10.1097/MD.0000000000010075 -
Pediatrics and Neonatology Feb 2018Persistent pulmonary hypertension of the newborn (PPHN) contributes to neonatal hypoxemia and is associated with a high mortality. Some PPHN patients are unresponsive to...
BACKGROUND
Persistent pulmonary hypertension of the newborn (PPHN) contributes to neonatal hypoxemia and is associated with a high mortality. Some PPHN patients are unresponsive to inhaled nitric oxide (iNO). Bosentan, an oral endothelin-1 receptor antagonist, reduces pulmonary vascular resistance and hence may play a role in the treatment of PPHN.
METHODS
A retrospective medical records review was performed in newborns who received oral bosentan as an adjunctive therapy for treatment of PPHN between January 2013 and February 2016 at the neonatal intensive care unit of Songklanagarind Hospital. The main outcomes were the effect of bosentan on oxygenation and hemodynamic status after commencement of treatment and the safety of bosentan.
RESULTS
Forty neonates at a median (IQR) gestation of 38 (36.8-40) weeks and an initial median (IQR) oxygen index (OI) of 29.2 (13.4-40.1) received bosentan therapy. Oral bosentan was commenced at a median (IQR) age of 27 (14.5-40.2) hours and the mean (SD) duration of treatment was 6.2 (3.1) days. The OI, alveolar-arterial oxygen difference (AaDO) and oxygen saturation (SpO) improved significantly at 2 h after treatment (p = 0.002, p = 0.01 and p < 0.001, respectively). In 21 (52.5%) neonates who received iNO and bosentan, the median OI (IQR) was 34.2 (29.0-42.6) with a significant decrease of OI at 6 h (p = 0.005) after treatment. In 19 (47.5%) neonates who received bosentan alone, the median OI (IQR) was 13.0 (9.8-30.9) with a significant decrease of OI in 2 h (p = 0.01) after treatment. The blood pressures before and after bosentan treatment were not statistically significantly different. The mortality rate was 12.5% (5/40).
CONCLUSION
Oral bosentan may be a safe and effective treatment to improve oxygenation in neonates with PPHN. Bosentan can be used as an adjuvant therapy with iNO and can be an alternative therapy option in mild-to-moderate PPHN.
Topics: Administration, Oral; Bosentan; Endothelin Receptor Antagonists; Female; Humans; Infant, Newborn; Male; Persistent Fetal Circulation Syndrome; Retrospective Studies; Sulfonamides; Treatment Outcome
PubMed: 28735030
DOI: 10.1016/j.pedneo.2017.02.003 -
Congestive Heart Failure (Greenwich,... 2003The World Health Organization symposium offers a new treatment-oriented classification of pulmonary hypertension based on an improved understanding of its... (Review)
Review
The World Health Organization symposium offers a new treatment-oriented classification of pulmonary hypertension based on an improved understanding of its pathophysiology. Regardless of the etiology, severe or unrelieved pulmonary hypertension leads to right heart failure. Symptoms and signs of pulmonary hypertension are often subtle and nonspecific. As a result, a significant delay between the onset of symptoms and the diagnosis of pulmonary hypertension is common. Echocardiography with Doppler flow is the most useful study to evaluate patients suspected of having pulmonary hypertension. The suspected diagnosis of pulmonary hypertension should then be confirmed by right heart catheterization. If present, further evaluation may include oxygen assessment, pulmonary function testing, high resolution computed tomography of the chest, and ventilation-perfusion lung scanning. Treatment of pulmonary hypertension requires uncommon expertise. General measures include correction of the underlying cause, reversal of hypoxemia and judicious use of diuretics. Advances in vasodilator therapy have increased treatment options beyond calcium channel blockers and intravenous epoprostenol. Lung transplantation remains an option for select patients with pulmonary hypertension not responding to medical management.
Topics: Antihypertensive Agents; Bosentan; Epoprostenol; Humans; Hypertension, Pulmonary; Prognosis; Pulmonary Circulation; Sulfonamides; Vasodilator Agents
PubMed: 12826774
DOI: 10.1111/j.1527-5299.2002.01050.x -
Clinical Cardiology Nov 2000The endothelin system appears to play an important role in the pathophysiology of congestive heart failure (CHF). Endothelin receptor antagonists represent a novel class... (Review)
Review
The endothelin system appears to play an important role in the pathophysiology of congestive heart failure (CHF). Endothelin receptor antagonists represent a novel class of agents that are being evaluated for their potential benefits in treating various cardiovascular disorders. Bosentan is an orally active endothelin receptor antagonist that has been studied for the treatment of CHF. Early clinical experience with bosentan has confirmed some benefits on hemodynamic parameters in patients with CHF. Its role in slowing the progression of the disease and improving survival remains to be elucidated.
Topics: Animals; Antihypertensive Agents; Bosentan; Controlled Clinical Trials as Topic; Dogs; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Hemodynamics; Humans; Placebos; Rats; Receptors, Endothelin; Sulfonamides; Time Factors
PubMed: 11097125
DOI: 10.1002/clc.4960231128 -
ESC Heart Failure Feb 2023Heart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) are related conditions with an increasing incidence. The mechanism...
AIMS
Heart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) are related conditions with an increasing incidence. The mechanism of their relationship remains undefined. Here, we aimed to explore the potential mechanisms, diagnostic markers, and therapeutic options for HFpEF and NAFLD.
METHODS AND RESULTS
HFpEF and NAFLD datasets were downloaded from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (DEGs) were screened for functional annotation. A protein-protein interaction network was constructed based on the STRING database, and hub genes were analysed using GeneMANIA annotation. ImmuCellAI (Immune Cell Abundance Identifier) was employed for analysis of immune infiltration. We also used validation datasets to validate the expression levels of hub genes and the correlation of immune cells. To screen for diagnostic biomarkers, we employed the least absolute shrinkage and selection operator and support vector machine-recursive feature elimination. Drug signature database was used to predict potential therapeutic drugs. Our analyses identified a total of 33 DEGs. Inflammation and immune infiltration played important roles in the development of both diseases. The data showed a close relationship between chemokine signalling pathway, cytokine-cytokine receptor interaction, calcium signalling pathway, neuroactive ligand-receptor interaction, osteoclast differentiation, and cyclic guanosine monophosphate-protein kinase G signalling pathway. We demonstrated that PRF1 (perforin 1) and IL2RB (interleukin-2 receptor subunit beta) proteins were perturbed by the diseases and may be the hub genes. The analysis showed that miR-375 may be a potential diagnostic marker for both diseases. Our drug prediction analysis showed that bosentan, eldecalcitol, ramipril, and probucol could be potential therapeutic options for the diseases.
CONCLUSIONS
Our findings revealed common pathogenesis, diagnostic markers, and therapeutic agents for HFpEF and NAFLD. There is need for further experimental studies to validate our findings.
Topics: Humans; Heart Failure; Non-alcoholic Fatty Liver Disease; Stroke Volume; Computational Biology; Bosentan
PubMed: 36266995
DOI: 10.1002/ehf2.14211