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Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation
Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholine...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005547/ https://www.ncbi.nlm.nih.gov/pubmed/33791350 http://dx.doi.org/10.3389/fcvm.2021.639541 |
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author | Qiu, Haihua Zhang, Yibo Li, Zhongyu Jiang, Ping Guo, Shuhong He, Yi Guo, Yuan |
author_facet | Qiu, Haihua Zhang, Yibo Li, Zhongyu Jiang, Ping Guo, Shuhong He, Yi Guo, Yuan |
author_sort | Qiu, Haihua |
collection | PubMed |
description | Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated. Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated. Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation. Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation. |
format | Online Article Text |
id | pubmed-8005547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80055472021-03-30 Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation Qiu, Haihua Zhang, Yibo Li, Zhongyu Jiang, Ping Guo, Shuhong He, Yi Guo, Yuan Front Cardiovasc Med Cardiovascular Medicine Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated. Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated. Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation. Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation. Frontiers Media S.A. 2021-03-15 /pmc/articles/PMC8005547/ /pubmed/33791350 http://dx.doi.org/10.3389/fcvm.2021.639541 Text en Copyright © 2021 Qiu, Zhang, Li, Jiang, Guo, He and Guo. http://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 Qiu, Haihua Zhang, Yibo Li, Zhongyu Jiang, Ping Guo, Shuhong He, Yi Guo, Yuan Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation |
title | Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation |
title_full | Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation |
title_fullStr | Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation |
title_full_unstemmed | Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation |
title_short | Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation |
title_sort | donepezil ameliorates pulmonary arterial hypertension by inhibiting m2-macrophage activation |
topic | Cardiovascular Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005547/ https://www.ncbi.nlm.nih.gov/pubmed/33791350 http://dx.doi.org/10.3389/fcvm.2021.639541 |
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