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Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade
BACKGROUND: This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation. METHODS: Left pneumonectomized male Wistar rats were inje...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557528/ https://www.ncbi.nlm.nih.gov/pubmed/34717626 http://dx.doi.org/10.1186/s12931-021-01875-w |
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author | Rampa, Dileep Reddy Murugesan, Priya Chao, Honglu Feng, Huiying Dai, Wenxin Lee, Dongwon Pekcec, Anton Doods, Henri Wu, Dongmei |
author_facet | Rampa, Dileep Reddy Murugesan, Priya Chao, Honglu Feng, Huiying Dai, Wenxin Lee, Dongwon Pekcec, Anton Doods, Henri Wu, Dongmei |
author_sort | Rampa, Dileep Reddy |
collection | PubMed |
description | BACKGROUND: This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation. METHODS: Left pneumonectomized male Wistar rats were injected with monocrotaline to induce PAH. Three weeks later, when PAH was well established, the rats received daily treatment of BI113823 or vehicle for 3 weeks. RESULTS: Treatment with BI113823 from day 21 to day 42 after monocrotaline injection reversed established PAH as shown by normalized values of mean pulmonary arterial pressure (mPAP). BI113823 therapy reversed pulmonary vascular remodeling, pulmonary arterial neointimal formation, and heart and lung fibrosis, reduced right ventricular pressure, right heart hypertrophy, improved cardiac output, and prevented right heart failure and death. Treatment with BI113823 reduced TNF-α and IL-1β, and macrophages recruitment in bronchoalveolar lavage, reduced CD-68 positive macrophages and expression of proliferating cell nuclear antigen (PCNA) in the perivascular areas, and reduced expression of iNOS, B1 receptors, matrix metalloproteinase (MMP)-2 and MMP-9 proteins, and the phosphorylation of ERK1/2 and AKT in lung. Treatment with BI113823 reduced mRNA expression of ANP, BNP, βMHC, CGTF, collange-I and IV in right heart, compared to vehicle treated controls. In human monocytes cultures, BI113823 reduced LPS-induced TNF-α production, MMP-2 and MMP-9 expression, and reduced TNF-α-induced monocyte migration. CONCLUSIONS: We conclude that BI113823 reverses preexisting severe experimental pulmonary hypertension via inhibition of macrophage infiltration, cytokine production, as well as down regulation of matrix metalloproteinase proteins. |
format | Online Article Text |
id | pubmed-8557528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-85575282021-11-01 Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade Rampa, Dileep Reddy Murugesan, Priya Chao, Honglu Feng, Huiying Dai, Wenxin Lee, Dongwon Pekcec, Anton Doods, Henri Wu, Dongmei Respir Res Research BACKGROUND: This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation. METHODS: Left pneumonectomized male Wistar rats were injected with monocrotaline to induce PAH. Three weeks later, when PAH was well established, the rats received daily treatment of BI113823 or vehicle for 3 weeks. RESULTS: Treatment with BI113823 from day 21 to day 42 after monocrotaline injection reversed established PAH as shown by normalized values of mean pulmonary arterial pressure (mPAP). BI113823 therapy reversed pulmonary vascular remodeling, pulmonary arterial neointimal formation, and heart and lung fibrosis, reduced right ventricular pressure, right heart hypertrophy, improved cardiac output, and prevented right heart failure and death. Treatment with BI113823 reduced TNF-α and IL-1β, and macrophages recruitment in bronchoalveolar lavage, reduced CD-68 positive macrophages and expression of proliferating cell nuclear antigen (PCNA) in the perivascular areas, and reduced expression of iNOS, B1 receptors, matrix metalloproteinase (MMP)-2 and MMP-9 proteins, and the phosphorylation of ERK1/2 and AKT in lung. Treatment with BI113823 reduced mRNA expression of ANP, BNP, βMHC, CGTF, collange-I and IV in right heart, compared to vehicle treated controls. In human monocytes cultures, BI113823 reduced LPS-induced TNF-α production, MMP-2 and MMP-9 expression, and reduced TNF-α-induced monocyte migration. CONCLUSIONS: We conclude that BI113823 reverses preexisting severe experimental pulmonary hypertension via inhibition of macrophage infiltration, cytokine production, as well as down regulation of matrix metalloproteinase proteins. BioMed Central 2021-10-30 2021 /pmc/articles/PMC8557528/ /pubmed/34717626 http://dx.doi.org/10.1186/s12931-021-01875-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Rampa, Dileep Reddy Murugesan, Priya Chao, Honglu Feng, Huiying Dai, Wenxin Lee, Dongwon Pekcec, Anton Doods, Henri Wu, Dongmei Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade |
title | Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade |
title_full | Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade |
title_fullStr | Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade |
title_full_unstemmed | Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade |
title_short | Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade |
title_sort | reversal of pulmonary arterial hypertension and neointimal formation by kinin b1 receptor blockade |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557528/ https://www.ncbi.nlm.nih.gov/pubmed/34717626 http://dx.doi.org/10.1186/s12931-021-01875-w |
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