Selective improvement of pulmonary arterial hypertension with a dual ET/ET 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...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-01-01
|
| Series: | Pulmonary Circulation |
| Online Access: | https://doi.org/10.1177/2045893217752328 |
| _version_ | 1811328132431478784 |
|---|---|
| author | Lewis Renshall Nadine Arnold Laura West Adam Braithwaite Josephine Pickworth Rachel Walker Mabruka Alfaidi Janet Chamberlain Helen Casbolt A.A. Roger Thompson Cathy Holt Marc Iglarz Sheila Francis Allan Lawrie |
| author_facet | Lewis Renshall Nadine Arnold Laura West Adam Braithwaite Josephine Pickworth Rachel Walker Mabruka Alfaidi Janet Chamberlain Helen Casbolt A.A. Roger Thompson Cathy Holt Marc Iglarz Sheila Francis Allan Lawrie |
| author_sort | Lewis Renshall |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T15:20:55Z |
| format | Article |
| id | doaj.art-3fb6ed9e753d40389dd062142e5177d1 |
| institution | Directory Open Access Journal |
| issn | 2045-8940 |
| language | English |
| last_indexed | 2024-04-13T15:20:55Z |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pulmonary Circulation |
| spelling | doaj.art-3fb6ed9e753d40389dd062142e5177d12022-12-22T02:41:41ZengWileyPulmonary Circulation2045-89402018-01-01810.1177/2045893217752328Selective improvement of pulmonary arterial hypertension with a dual ET/ET receptors antagonist in the apolipoprotein E model of PAH and atherosclerosisLewis RenshallNadine ArnoldLaura WestAdam BraithwaiteJosephine PickworthRachel Walker0Mabruka AlfaidiJanet ChamberlainHelen CasboltA.A. Roger ThompsonCathy Holt1Marc IglarzSheila FrancisAllan Lawrie, Manchester, UK, Manchester, UKIdiopathic 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.https://doi.org/10.1177/2045893217752328 |
| spellingShingle | Lewis Renshall Nadine Arnold Laura West Adam Braithwaite Josephine Pickworth Rachel Walker Mabruka Alfaidi Janet Chamberlain Helen Casbolt A.A. Roger Thompson Cathy Holt Marc Iglarz Sheila Francis Allan Lawrie Selective improvement of pulmonary arterial hypertension with a dual ET/ET receptors antagonist in the apolipoprotein E model of PAH and atherosclerosis Pulmonary Circulation |
| title | Selective improvement of pulmonary arterial hypertension with a dual ET/ET receptors antagonist in the apolipoprotein E model of PAH and atherosclerosis |
| title_full | Selective improvement of pulmonary arterial hypertension with a dual ET/ET receptors antagonist in the apolipoprotein E model of PAH and atherosclerosis |
| title_fullStr | Selective improvement of pulmonary arterial hypertension with a dual ET/ET receptors antagonist in the apolipoprotein E model of PAH and atherosclerosis |
| title_full_unstemmed | Selective improvement of pulmonary arterial hypertension with a dual ET/ET receptors antagonist in the apolipoprotein E model of PAH and atherosclerosis |
| title_short | Selective improvement of pulmonary arterial hypertension with a dual ET/ET receptors antagonist in the apolipoprotein E model of PAH and atherosclerosis |
| title_sort | selective improvement of pulmonary arterial hypertension with a dual et et receptors antagonist in the apolipoprotein e model of pah and atherosclerosis |
| url | https://doi.org/10.1177/2045893217752328 |
| work_keys_str_mv | AT lewisrenshall selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT nadinearnold selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT laurawest selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT adambraithwaite selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT josephinepickworth selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT rachelwalker selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT mabrukaalfaidi selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT janetchamberlain selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT helencasbolt selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT aarogerthompson selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT cathyholt selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT marciglarz selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT sheilafrancis selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis AT allanlawrie selectiveimprovementofpulmonaryarterialhypertensionwithadualetetreceptorsantagonistintheapolipoproteinemodelofpahandatherosclerosis |