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Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis
Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque r...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985228/ https://www.ncbi.nlm.nih.gov/pubmed/27532042 http://dx.doi.org/10.1126/sciadv.1600224 |
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author | Karunakaran, Denuja Geoffrion, Michele Wei, Lihui Gan, Wei Richards, Laura Shangari, Prakriti DeKemp, Ella M. Beanlands, Rachelle A. Perisic, Ljubica Maegdefessel, Lars Hedin, Ulf Sad, Subash Guo, Liang Kolodgie, Frank D. Virmani, Renu Ruddy, Terrence Rayner, Katey J. |
author_facet | Karunakaran, Denuja Geoffrion, Michele Wei, Lihui Gan, Wei Richards, Laura Shangari, Prakriti DeKemp, Ella M. Beanlands, Rachelle A. Perisic, Ljubica Maegdefessel, Lars Hedin, Ulf Sad, Subash Guo, Liang Kolodgie, Frank D. Virmani, Renu Ruddy, Terrence Rayner, Katey J. |
author_sort | Karunakaran, Denuja |
collection | PubMed |
description | Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that, in contrast to apoptosis, induces a proinflammatory state. We show herein that necroptotic cell death is activated in human advanced atherosclerotic plaques and can be targeted in experimental atherosclerosis for both therapeutic and diagnostic interventions. In humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased, and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. Investigation of the molecular mechanisms underlying necroptosis showed that atherogenic forms of low-density lipoprotein increase RIP3 and MLKL transcription and phosphorylation—two critical steps in the execution of necroptosis. Using a radiotracer developed with the necroptosis inhibitor necrostatin-1 (Nec-1), we show that (123)I-Nec-1 localizes specifically to atherosclerotic plaques in Apoe(−/−) mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of Apoe(−/−) mice with established atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Collectively, our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable atherosclerosis. |
format | Online Article Text |
id | pubmed-4985228 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49852282016-08-16 Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis Karunakaran, Denuja Geoffrion, Michele Wei, Lihui Gan, Wei Richards, Laura Shangari, Prakriti DeKemp, Ella M. Beanlands, Rachelle A. Perisic, Ljubica Maegdefessel, Lars Hedin, Ulf Sad, Subash Guo, Liang Kolodgie, Frank D. Virmani, Renu Ruddy, Terrence Rayner, Katey J. Sci Adv Research Articles Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that, in contrast to apoptosis, induces a proinflammatory state. We show herein that necroptotic cell death is activated in human advanced atherosclerotic plaques and can be targeted in experimental atherosclerosis for both therapeutic and diagnostic interventions. In humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased, and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. Investigation of the molecular mechanisms underlying necroptosis showed that atherogenic forms of low-density lipoprotein increase RIP3 and MLKL transcription and phosphorylation—two critical steps in the execution of necroptosis. Using a radiotracer developed with the necroptosis inhibitor necrostatin-1 (Nec-1), we show that (123)I-Nec-1 localizes specifically to atherosclerotic plaques in Apoe(−/−) mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of Apoe(−/−) mice with established atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Collectively, our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable atherosclerosis. American Association for the Advancement of Science 2016-07-22 /pmc/articles/PMC4985228/ /pubmed/27532042 http://dx.doi.org/10.1126/sciadv.1600224 Text en Copyright © 2016, The Authors http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Karunakaran, Denuja Geoffrion, Michele Wei, Lihui Gan, Wei Richards, Laura Shangari, Prakriti DeKemp, Ella M. Beanlands, Rachelle A. Perisic, Ljubica Maegdefessel, Lars Hedin, Ulf Sad, Subash Guo, Liang Kolodgie, Frank D. Virmani, Renu Ruddy, Terrence Rayner, Katey J. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis |
title | Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis |
title_full | Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis |
title_fullStr | Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis |
title_full_unstemmed | Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis |
title_short | Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis |
title_sort | targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985228/ https://www.ncbi.nlm.nih.gov/pubmed/27532042 http://dx.doi.org/10.1126/sciadv.1600224 |
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