Endothelin receptor antagonists – their role in pulmonary medicine

Boniface, S.; Reynaud-Gaubert, M.

doi:10.1016/j.rmr.2009.07.001

Cited by 12 publications

(10 citation statements)

References 95 publications

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“…PASMCs in pulmonary hypertension have also been shown to also lose vascular tone balance through the inhibition of potassium ion channels, Kv1.5 and Kv2.1 [3], [4]. Endothelin-1 and platelet derived growth factor β (PDGF) receptor blockers are used to treat PAH but do not reduce death rates [5], [6]. MicroRNAs (miRs) are single-stranded RNA molecules, about twenty-two nucleotides, which regulates gene expression.…”

Section: Introductionmentioning

confidence: 99%

Mir-206 Regulates Pulmonary Artery Smooth Muscle Cell Proliferation and Differentiation

et al. 2012

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Pulmonary Arterial Hypertension (PAH) is a progressive devastating disease characterized by excessive proliferation of the Pulmonary Arterial Smooth Muscle Cells (PASMCs). Studies suggest that PAH and cancers share an apoptosis-resistant state featuring excessive cell proliferation. MicroRNA-206 (miR-206) is known to regulate proliferation and is implicated in various types of cancers. However, the role of miR-206 in PAH has not been studied. In this study, it is hypothesized that miR-206 could play a role in the proliferation of PASMCs. In the present study, the expression patterns of miR-206 were investigated in normal and hypertensive mouse PASMCs. The effects of miR-206 in modulating cell proliferation, apoptosis and smooth muscle cell markers in human pulmonary artery smooth muscle cells (hPASMCs) were investigated in vitro. miR-206 expression in mouse PASMCs was correlated with an increase in right ventricular systolic pressure. Reduction of miR-206 levels in hPASMCs causes increased proliferation and reduced apoptosis and these effects were reversed by the overexpression of miR-206. miR-206 over expression also increased the levels of smooth muscle cell differentiation markers α-smooth muscle actin and calponin implicating its importance in the differentiation of SMCs. miR-206 overexpression down regulated Notch-3 expression, which is key a factor in PAH development. These results suggest that miR-206 is a potential regulator of proliferation, apoptosis and differentiation of PASMCs, and that it could be used as a novel treatment strategy in PAH.

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Section: Introductionmentioning

confidence: 99%

Mir-206 Regulates Pulmonary Artery Smooth Muscle Cell Proliferation and Differentiation

et al. 2012

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“…ERAs are a class of orally active agents that modulate the deleterious activity of ET-1 in the pulmonary vasculature [13,[35][36][37][38]. Treatment with approved ERAs has been shown to confer improvements in a number of important clinical endpoints, including exercise capacity, modified New York Heart Association functional class, and pulmonary hemodynamics [13,[35][36][37][38].…”

Section: The Et System In Pahmentioning

confidence: 99%

“…Treatment with approved ERAs has been shown to confer improvements in a number of important clinical endpoints, including exercise capacity, modified New York Heart Association functional class, and pulmonary hemodynamics [13,[35][36][37][38]. Currently licensed ERAs can be sub-classified into dual ET A / ET B receptor antagonists and selective ET A receptor antagonists [39,40].…”

Section: The Et System In Pahmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic evaluation of macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension

Sidharta

Krähenbühl

Dingemanse

2015

Expert Opinion on Drug Metabolism & Toxicology

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Up to date, macitentan is the only registered treatment for PAH that significantly reduced morbidity and mortality as a combined endpoint in a long-term event-driven study. The safety profile of macitentan is favorable with respect to hepatic safety and edema/fluid retention and may be better than that of other ET receptor antagonists such as bosentan and ambrisentan. The PK profile supports a once-a-day dosing regimen. Macitentan has limited interactions with other drugs. Based on these characteristics macitentan is an important new addition to the treatment of PAH.

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“…It is intended to inhibit vasoconstriction, hypertrophic and fibrotic effects by blocking the actions of receptors (ET A and ET B ) which leads to reduction of blood pressure in lungs. Bosentan interact with the binding of ET-1 and other ET peptides to both ET A and ET B receptors [7]. The objective of this work is to identify the role the mechanism of Bosentan on ET B receptor and to model the protein, and to identify the interactions with Bosentan and their derivatives.…”

Section: Introductionmentioning

confidence: 99%

Homology modeling, active site prediction, and targeting the anti hypertension activity through molecular docking on endothelin – B receptor domain

Daddam¹,

Selvaraj²,

Ganeshan³

et al. 2012

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In cardiovascular system, activation of Endothelin receptors causes vasoconstriction which leads to Pulmonary Arterial Hypertension (PAH). Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension. Bosentan is intended to affect vasoconstriction, hypertrophic and fibrotic effects by blocking the actions of receptors ETA and ETB. In this study we identified the action of Bosentan on endothelin B receptor using docking studies with homology modeled endothelin B receptor. Through the modeled protein, the flexible Docking study was performed with Bosentan and its derivatives with theoretically predicted active sites. The results indicated that amino acid ARG82, ARG84 and HIS197 present in endothelin B receptor are core important for binding activities and these residues are having strong hydrogen bond interactions with Bosentan. We have investigated the Bosentan and its derivatives interactions and scoring parameters using gold docking package. Among the docked compounds, one of the Bosentan derivatives BD6 shows better interaction than Bosentan with endothelin B receptor. Our results may be helpful for further investigations in both in vivo and in vitro conditions.

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Endothelin receptor antagonists – their role in pulmonary medicine

Cited by 12 publications

References 95 publications

Mir-206 Regulates Pulmonary Artery Smooth Muscle Cell Proliferation and Differentiation

Mir-206 Regulates Pulmonary Artery Smooth Muscle Cell Proliferation and Differentiation

Pharmacokinetic and pharmacodynamic evaluation of macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension

Homology modeling, active site prediction, and targeting the anti hypertension activity through molecular docking on endothelin – B receptor domain

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