Cargando…
Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque
Currently there are no established therapies to treat high-risk patients with unstable atherosclerotic lesions that are prone to rupture and can result in thrombosis, abrupt arterial occlusion, and a precipitous infarction. Rather than being stenotic, rupture-prone non-occlusive plaques are commonly...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9663534/ https://www.ncbi.nlm.nih.gov/pubmed/36375379 http://dx.doi.org/10.1016/j.redox.2022.102532 |
_version_ | 1784830900292288512 |
---|---|
author | Chen, Weiyu Tumanov, Sergey Kong, Stephanie M.Y. Cheng, David Michaëlsson, Erik Bongers, André Power, Carl Ayer, Anita Stocker, Roland |
author_facet | Chen, Weiyu Tumanov, Sergey Kong, Stephanie M.Y. Cheng, David Michaëlsson, Erik Bongers, André Power, Carl Ayer, Anita Stocker, Roland |
author_sort | Chen, Weiyu |
collection | PubMed |
description | Currently there are no established therapies to treat high-risk patients with unstable atherosclerotic lesions that are prone to rupture and can result in thrombosis, abrupt arterial occlusion, and a precipitous infarction. Rather than being stenotic, rupture-prone non-occlusive plaques are commonly enriched with inflammatory cells and have a thin fibrous cap. We reported previously that inhibition of the pro-inflammatory enzyme myeloperoxidase (MPO) with the suicide inhibitor AZM198 prevents formation of unstable plaque in the Tandem Stenosis (TS) mouse model of plaque instability. However, in our previous study AZM198 was administered to animals before unstable plaque was present and hence it did not test the significant unmet clinical need present in high-risk patients with vulnerable atherosclerosis. In the present study we therefore asked whether pharmacological inhibition of MPO with AZM198 can stabilize pre-existing unstable lesions in an interventional setting using the mouse model of plaque instability. In vivo molecular magnetic resonance imaging of arterial MPO activity using bis-5-hydroxytryptamide-DTPA-Gd and histological analyses revealed that arterial MPO activity was elevated one week after TS surgery, prior to the presence of unstable lesions observed two weeks after TS surgery. Animals with pre-existing unstable plaque were treated with AZM198 for one or five weeks. Both short- and long-term intervention effectively inhibited arterial MPO activity and increased fibrous cap thickness, indicative of a more stable plaque phenotype. Plaque stabilization was observed without AZM198 affecting the arterial content of Ly6B.2(+)- and CD68(+)-cells and MPO protein. These findings demonstrate that inhibition of arterial MPO activity converts unstable into stable atherosclerotic lesions in a preclinical model of plaque instability and highlight the potential therapeutic potency of MPO inhibition for the management of high-risk patients and the development of novel protective strategies against cardiovascular diseases. |
format | Online Article Text |
id | pubmed-9663534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-96635342022-11-15 Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque Chen, Weiyu Tumanov, Sergey Kong, Stephanie M.Y. Cheng, David Michaëlsson, Erik Bongers, André Power, Carl Ayer, Anita Stocker, Roland Redox Biol Research Paper Currently there are no established therapies to treat high-risk patients with unstable atherosclerotic lesions that are prone to rupture and can result in thrombosis, abrupt arterial occlusion, and a precipitous infarction. Rather than being stenotic, rupture-prone non-occlusive plaques are commonly enriched with inflammatory cells and have a thin fibrous cap. We reported previously that inhibition of the pro-inflammatory enzyme myeloperoxidase (MPO) with the suicide inhibitor AZM198 prevents formation of unstable plaque in the Tandem Stenosis (TS) mouse model of plaque instability. However, in our previous study AZM198 was administered to animals before unstable plaque was present and hence it did not test the significant unmet clinical need present in high-risk patients with vulnerable atherosclerosis. In the present study we therefore asked whether pharmacological inhibition of MPO with AZM198 can stabilize pre-existing unstable lesions in an interventional setting using the mouse model of plaque instability. In vivo molecular magnetic resonance imaging of arterial MPO activity using bis-5-hydroxytryptamide-DTPA-Gd and histological analyses revealed that arterial MPO activity was elevated one week after TS surgery, prior to the presence of unstable lesions observed two weeks after TS surgery. Animals with pre-existing unstable plaque were treated with AZM198 for one or five weeks. Both short- and long-term intervention effectively inhibited arterial MPO activity and increased fibrous cap thickness, indicative of a more stable plaque phenotype. Plaque stabilization was observed without AZM198 affecting the arterial content of Ly6B.2(+)- and CD68(+)-cells and MPO protein. These findings demonstrate that inhibition of arterial MPO activity converts unstable into stable atherosclerotic lesions in a preclinical model of plaque instability and highlight the potential therapeutic potency of MPO inhibition for the management of high-risk patients and the development of novel protective strategies against cardiovascular diseases. Elsevier 2022-11-05 /pmc/articles/PMC9663534/ /pubmed/36375379 http://dx.doi.org/10.1016/j.redox.2022.102532 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Chen, Weiyu Tumanov, Sergey Kong, Stephanie M.Y. Cheng, David Michaëlsson, Erik Bongers, André Power, Carl Ayer, Anita Stocker, Roland Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque |
title | Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque |
title_full | Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque |
title_fullStr | Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque |
title_full_unstemmed | Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque |
title_short | Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque |
title_sort | therapeutic inhibition of mpo stabilizes pre-existing high risk atherosclerotic plaque |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9663534/ https://www.ncbi.nlm.nih.gov/pubmed/36375379 http://dx.doi.org/10.1016/j.redox.2022.102532 |
work_keys_str_mv | AT chenweiyu therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque AT tumanovsergey therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque AT kongstephaniemy therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque AT chengdavid therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque AT michaelssonerik therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque AT bongersandre therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque AT powercarl therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque AT ayeranita therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque AT stockerroland therapeuticinhibitionofmpostabilizespreexistinghighriskatheroscleroticplaque |