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The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigatio...

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Autores principales: Mulvaney, Eamon P., Renzo, Fabiana, Adão, Rui, Dupre, Emilie, Bialesova, Lucia, Salvatore, Viviana, Reid, Helen M., Conceição, Glória, Grynblat, Julien, Llucià-Valldeperas, Aida, Michel, Jean-Baptiste, Brás-Silva, Carmen, Laurent, Charles E., Howard, Luke S., Montani, David, Humbert, Marc, Vonk Noordegraaf, Anton, Perros, Frédéric, Mendes-Ferreira, Pedro, Kinsella, B. Therese
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9794752/
https://www.ncbi.nlm.nih.gov/pubmed/36588576
http://dx.doi.org/10.3389/fcvm.2022.1063967
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author Mulvaney, Eamon P.
Renzo, Fabiana
Adão, Rui
Dupre, Emilie
Bialesova, Lucia
Salvatore, Viviana
Reid, Helen M.
Conceição, Glória
Grynblat, Julien
Llucià-Valldeperas, Aida
Michel, Jean-Baptiste
Brás-Silva, Carmen
Laurent, Charles E.
Howard, Luke S.
Montani, David
Humbert, Marc
Vonk Noordegraaf, Anton
Perros, Frédéric
Mendes-Ferreira, Pedro
Kinsella, B. Therese
author_facet Mulvaney, Eamon P.
Renzo, Fabiana
Adão, Rui
Dupre, Emilie
Bialesova, Lucia
Salvatore, Viviana
Reid, Helen M.
Conceição, Glória
Grynblat, Julien
Llucià-Valldeperas, Aida
Michel, Jean-Baptiste
Brás-Silva, Carmen
Laurent, Charles E.
Howard, Luke S.
Montani, David
Humbert, Marc
Vonk Noordegraaf, Anton
Perros, Frédéric
Mendes-Ferreira, Pedro
Kinsella, B. Therese
author_sort Mulvaney, Eamon P.
collection PubMed
description BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A(2) receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. METHODS: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). RESULTS: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. CONCLUSION: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions.
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spelling pubmed-97947522022-12-29 The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload Mulvaney, Eamon P. Renzo, Fabiana Adão, Rui Dupre, Emilie Bialesova, Lucia Salvatore, Viviana Reid, Helen M. Conceição, Glória Grynblat, Julien Llucià-Valldeperas, Aida Michel, Jean-Baptiste Brás-Silva, Carmen Laurent, Charles E. Howard, Luke S. Montani, David Humbert, Marc Vonk Noordegraaf, Anton Perros, Frédéric Mendes-Ferreira, Pedro Kinsella, B. Therese Front Cardiovasc Med Cardiovascular Medicine BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A(2) receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. METHODS: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). RESULTS: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. CONCLUSION: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions. Frontiers Media S.A. 2022-12-14 /pmc/articles/PMC9794752/ /pubmed/36588576 http://dx.doi.org/10.3389/fcvm.2022.1063967 Text en Copyright © 2022 Mulvaney, Renzo, Adão, Dupre, Bialesova, Salvatore, Reid, Conceição, Grynblat, Llucià-Valldeperas, Michel, Brás-Silva, Laurent, Howard, Montani, Humbert, Vonk Noordegraaf, Perros, Mendes-Ferreira and Kinsella. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Mulvaney, Eamon P.
Renzo, Fabiana
Adão, Rui
Dupre, Emilie
Bialesova, Lucia
Salvatore, Viviana
Reid, Helen M.
Conceição, Glória
Grynblat, Julien
Llucià-Valldeperas, Aida
Michel, Jean-Baptiste
Brás-Silva, Carmen
Laurent, Charles E.
Howard, Luke S.
Montani, David
Humbert, Marc
Vonk Noordegraaf, Anton
Perros, Frédéric
Mendes-Ferreira, Pedro
Kinsella, B. Therese
The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload
title The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload
title_full The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload
title_fullStr The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload
title_full_unstemmed The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload
title_short The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload
title_sort thromboxane receptor antagonist ntp42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9794752/
https://www.ncbi.nlm.nih.gov/pubmed/36588576
http://dx.doi.org/10.3389/fcvm.2022.1063967
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