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Selective improvement of pulmonary arterial hypertension with a dual ET(A)/ET(B) receptors antagonist in the apolipoprotein E(−/−) model of PAH and atherosclerosis
Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of co-morbid atherosclerosis. Apolipoprotein E-deficient (ApoE(−/−)) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels o...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798688/ https://www.ncbi.nlm.nih.gov/pubmed/29261014 http://dx.doi.org/10.1177/2045893217752328 |
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author | Renshall, Lewis Arnold, Nadine West, Laura Braithwaite, Adam Pickworth, Josephine Walker, Rachel Alfaidi, Mabruka Chamberlain, Janet Casbolt, Helen Thompson, A.A. Roger Holt, Cathy Iglarz, Marc Francis, Sheila Lawrie, Allan |
author_facet | Renshall, Lewis Arnold, Nadine West, Laura Braithwaite, Adam Pickworth, Josephine Walker, Rachel Alfaidi, Mabruka Chamberlain, Janet Casbolt, Helen Thompson, A.A. Roger Holt, Cathy Iglarz, Marc Francis, Sheila Lawrie, Allan |
author_sort | Renshall, Lewis |
collection | PubMed |
description | Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of co-morbid atherosclerosis. Apolipoprotein E-deficient (ApoE(−/−)) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels of endothelin (ET)-1. ET-1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE(−/−) mice with macitentan, a dual ET(A)/ET(B) receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE(−/−) mice were fed chow or HFD for eight weeks. After four weeks of HFD, mice were randomized to a four-week treatment of macitentan by food (30 mg/kg/day dual ET(A)/ET(B) antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterization were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE(−/−) mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial-dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ET(A)/ET(B) receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis. |
format | Online Article Text |
id | pubmed-5798688 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-57986882018-02-12 Selective improvement of pulmonary arterial hypertension with a dual ET(A)/ET(B) receptors antagonist in the apolipoprotein E(−/−) model of PAH and atherosclerosis Renshall, Lewis Arnold, Nadine West, Laura Braithwaite, Adam Pickworth, Josephine Walker, Rachel Alfaidi, Mabruka Chamberlain, Janet Casbolt, Helen Thompson, A.A. Roger Holt, Cathy Iglarz, Marc Francis, Sheila Lawrie, Allan Pulm Circ Research Article Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of co-morbid atherosclerosis. Apolipoprotein E-deficient (ApoE(−/−)) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels of endothelin (ET)-1. ET-1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE(−/−) mice with macitentan, a dual ET(A)/ET(B) receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE(−/−) mice were fed chow or HFD for eight weeks. After four weeks of HFD, mice were randomized to a four-week treatment of macitentan by food (30 mg/kg/day dual ET(A)/ET(B) antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterization were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE(−/−) mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial-dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ET(A)/ET(B) receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis. SAGE Publications 2017-12-20 /pmc/articles/PMC5798688/ /pubmed/29261014 http://dx.doi.org/10.1177/2045893217752328 Text en © The Author(s) 2018 http://creativecommons.org/licenses/by/4.0/ Creative Commons CC-BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Research Article Renshall, Lewis Arnold, Nadine West, Laura Braithwaite, Adam Pickworth, Josephine Walker, Rachel Alfaidi, Mabruka Chamberlain, Janet Casbolt, Helen Thompson, A.A. Roger Holt, Cathy Iglarz, Marc Francis, Sheila Lawrie, Allan Selective improvement of pulmonary arterial hypertension with a dual ET(A)/ET(B) receptors antagonist in the apolipoprotein E(−/−) model of PAH and atherosclerosis |
title | Selective improvement of pulmonary arterial hypertension with a dual ET(A)/ET(B) receptors antagonist in the apolipoprotein E(−/−) model of PAH and atherosclerosis |
title_full | Selective improvement of pulmonary arterial hypertension with a dual ET(A)/ET(B) receptors antagonist in the apolipoprotein E(−/−) model of PAH and atherosclerosis |
title_fullStr | Selective improvement of pulmonary arterial hypertension with a dual ET(A)/ET(B) receptors antagonist in the apolipoprotein E(−/−) model of PAH and atherosclerosis |
title_full_unstemmed | Selective improvement of pulmonary arterial hypertension with a dual ET(A)/ET(B) receptors antagonist in the apolipoprotein E(−/−) model of PAH and atherosclerosis |
title_short | Selective improvement of pulmonary arterial hypertension with a dual ET(A)/ET(B) receptors antagonist in the apolipoprotein E(−/−) model of PAH and atherosclerosis |
title_sort | selective improvement of pulmonary arterial hypertension with a dual et(a)/et(b) receptors antagonist in the apolipoprotein e(−/−) model of pah and atherosclerosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798688/ https://www.ncbi.nlm.nih.gov/pubmed/29261014 http://dx.doi.org/10.1177/2045893217752328 |
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