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Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study
Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway as a promising target in the treatment of atherosclerotic disease. It is, however, unclear whether these observations apply to human atherosclerosis. Therefore we evaluated the profile of AP-1 activation through histolo...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259695/ https://www.ncbi.nlm.nih.gov/pubmed/22092038 http://dx.doi.org/10.1042/CS20110234 |
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author | Meijer, C. Arnoud Le Haen, Pum A. A. van Dijk, Rogier A. Hira, Mitsuhisa Hamming, Jaap F. van Bockel, J. Hajo Lindeman, Jan H. |
author_facet | Meijer, C. Arnoud Le Haen, Pum A. A. van Dijk, Rogier A. Hira, Mitsuhisa Hamming, Jaap F. van Bockel, J. Hajo Lindeman, Jan H. |
author_sort | Meijer, C. Arnoud |
collection | PubMed |
description | Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway as a promising target in the treatment of atherosclerotic disease. It is, however, unclear whether these observations apply to human atherosclerosis. Therefore we evaluated the profile of AP-1 activation through histological analysis and tested the potential benefit of AP-1 inhibition in a clinical trial. AP-1 activation was quantified by phospho-c-Jun nuclear translocation (immunohistochemistry) on a biobank of aortic wall samples from organ donors. The effect of AP-1 inhibition on vascular parameters was tested through a double blind placebo-controlled cross-over study of 28 days doxycycline or placebo in patients with symptomatic peripheral artery disease. Vascular function was assessed by brachial dilation as well as by plasma samples analysed for hs-CRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6), IL-8, ICAM-1 (intercellular adhesion molecule-1), vWF (von Willebrand factor), MCP-1 (monocyte chemoattractant protein-1), PAI-1 (plasminogen activator inhibitor-1) and fibrinogen. Histological evaluation of human atherosclerosis showed minimal AP-1 activation in non-diseased arterial wall (i.e. vessel wall without any signs of atherosclerotic disease). A gradual increase of AP-1 activation was found in non-progressive and progressive phases of atherosclerosis respectively (P<0.044). No significant difference was found between progressive and vulnerable lesions. The expression of phospho-c-Jun diminished as the lesion stabilized (P<0.016) and does not significantly differ from the normal aortic wall (P<0.33). Evaluation of the doxycycline intervention only revealed a borderline-significant reduction of circulating hs-CRP levels (−0.51 μg/ml, P=0.05) and did not affect any of the other markers of systemic inflammation and vascular function. Our studies do not characterize AP-1 as a therapeutic target for progressive human atherosclerotic disease. |
format | Online Article Text |
id | pubmed-3259695 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-32596952012-01-18 Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study Meijer, C. Arnoud Le Haen, Pum A. A. van Dijk, Rogier A. Hira, Mitsuhisa Hamming, Jaap F. van Bockel, J. Hajo Lindeman, Jan H. Clin Sci (Lond) Research Article Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway as a promising target in the treatment of atherosclerotic disease. It is, however, unclear whether these observations apply to human atherosclerosis. Therefore we evaluated the profile of AP-1 activation through histological analysis and tested the potential benefit of AP-1 inhibition in a clinical trial. AP-1 activation was quantified by phospho-c-Jun nuclear translocation (immunohistochemistry) on a biobank of aortic wall samples from organ donors. The effect of AP-1 inhibition on vascular parameters was tested through a double blind placebo-controlled cross-over study of 28 days doxycycline or placebo in patients with symptomatic peripheral artery disease. Vascular function was assessed by brachial dilation as well as by plasma samples analysed for hs-CRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6), IL-8, ICAM-1 (intercellular adhesion molecule-1), vWF (von Willebrand factor), MCP-1 (monocyte chemoattractant protein-1), PAI-1 (plasminogen activator inhibitor-1) and fibrinogen. Histological evaluation of human atherosclerosis showed minimal AP-1 activation in non-diseased arterial wall (i.e. vessel wall without any signs of atherosclerotic disease). A gradual increase of AP-1 activation was found in non-progressive and progressive phases of atherosclerosis respectively (P<0.044). No significant difference was found between progressive and vulnerable lesions. The expression of phospho-c-Jun diminished as the lesion stabilized (P<0.016) and does not significantly differ from the normal aortic wall (P<0.33). Evaluation of the doxycycline intervention only revealed a borderline-significant reduction of circulating hs-CRP levels (−0.51 μg/ml, P=0.05) and did not affect any of the other markers of systemic inflammation and vascular function. Our studies do not characterize AP-1 as a therapeutic target for progressive human atherosclerotic disease. Portland Press Ltd. 2012-01-16 2012-05-01 /pmc/articles/PMC3259695/ /pubmed/22092038 http://dx.doi.org/10.1042/CS20110234 Text en © 2012 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by-nc/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Meijer, C. Arnoud Le Haen, Pum A. A. van Dijk, Rogier A. Hira, Mitsuhisa Hamming, Jaap F. van Bockel, J. Hajo Lindeman, Jan H. Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study |
title | Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study |
title_full | Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study |
title_fullStr | Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study |
title_full_unstemmed | Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study |
title_short | Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study |
title_sort | activator protein-1 (ap-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259695/ https://www.ncbi.nlm.nih.gov/pubmed/22092038 http://dx.doi.org/10.1042/CS20110234 |
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