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Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury

Inflammatory cells play key roles in restenosis upon vascular surgical procedures such as bypass grafts, angioplasty and stent deployment but the molecular mechanisms by which these cells affect restenosis remain unclear. The p110δ isoform of phosphoinositide 3-kinase (PI3K) is mainly expressed in w...

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Autores principales: Bilancio, Antonio, Rinaldi, Barbara, Oliviero, Maria Antonietta, Donniacuo, Maria, Monti, Maria Gaia, Boscaino, Amedeo, Marino, Irene, Friedman, Lori, Rossi, Francesco, Vanhaesebroeck, Bart, Migliaccio, Antimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617917/
https://www.ncbi.nlm.nih.gov/pubmed/28851839
http://dx.doi.org/10.1042/BSR20171112
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author Bilancio, Antonio
Rinaldi, Barbara
Oliviero, Maria Antonietta
Donniacuo, Maria
Monti, Maria Gaia
Boscaino, Amedeo
Marino, Irene
Friedman, Lori
Rossi, Francesco
Vanhaesebroeck, Bart
Migliaccio, Antimo
author_facet Bilancio, Antonio
Rinaldi, Barbara
Oliviero, Maria Antonietta
Donniacuo, Maria
Monti, Maria Gaia
Boscaino, Amedeo
Marino, Irene
Friedman, Lori
Rossi, Francesco
Vanhaesebroeck, Bart
Migliaccio, Antimo
author_sort Bilancio, Antonio
collection PubMed
description Inflammatory cells play key roles in restenosis upon vascular surgical procedures such as bypass grafts, angioplasty and stent deployment but the molecular mechanisms by which these cells affect restenosis remain unclear. The p110δ isoform of phosphoinositide 3-kinase (PI3K) is mainly expressed in white blood cells. Here, we have investigated whether p110δ PI3K is involved in the pathogenesis of restenosis in a mouse model of carotid injury, which mimics the damage following arterial grafts. We used mice in which p110δ kinase activity has been disabled by a knockin (KI) point mutation in its ATP-binding site (p110δ(D910A/D910A) PI3K mice). Wild-type (WT) and p110δ(D910A/D910A) mice were subjected to longitudinal carotid injury. At 14 and 30 days after carotid injury, mice with inactive p110δ showed strongly decreased infiltration of inflammatory cells (including T lymphocytes and macrophages) and vascular smooth muscle cells (VSMCs), compared with WT mice. Likewise, PI-3065, a p110δ-selective PI3K inhibitor, almost completely prevented restenosis after artery injury. Our data showed that p110δ PI3K plays a main role in promoting neointimal thickening and inflammatory processes during vascular stenosis, with its inhibition providing significant reduction in restenosis following carotid injury. p110δ-selective inhibitors, recently approved for the treatment of human B-cell malignancies, therefore, present a new therapeutic opportunity to prevent the restenosis upon artery injury.
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spelling pubmed-56179172017-10-10 Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury Bilancio, Antonio Rinaldi, Barbara Oliviero, Maria Antonietta Donniacuo, Maria Monti, Maria Gaia Boscaino, Amedeo Marino, Irene Friedman, Lori Rossi, Francesco Vanhaesebroeck, Bart Migliaccio, Antimo Biosci Rep Research Articles Inflammatory cells play key roles in restenosis upon vascular surgical procedures such as bypass grafts, angioplasty and stent deployment but the molecular mechanisms by which these cells affect restenosis remain unclear. The p110δ isoform of phosphoinositide 3-kinase (PI3K) is mainly expressed in white blood cells. Here, we have investigated whether p110δ PI3K is involved in the pathogenesis of restenosis in a mouse model of carotid injury, which mimics the damage following arterial grafts. We used mice in which p110δ kinase activity has been disabled by a knockin (KI) point mutation in its ATP-binding site (p110δ(D910A/D910A) PI3K mice). Wild-type (WT) and p110δ(D910A/D910A) mice were subjected to longitudinal carotid injury. At 14 and 30 days after carotid injury, mice with inactive p110δ showed strongly decreased infiltration of inflammatory cells (including T lymphocytes and macrophages) and vascular smooth muscle cells (VSMCs), compared with WT mice. Likewise, PI-3065, a p110δ-selective PI3K inhibitor, almost completely prevented restenosis after artery injury. Our data showed that p110δ PI3K plays a main role in promoting neointimal thickening and inflammatory processes during vascular stenosis, with its inhibition providing significant reduction in restenosis following carotid injury. p110δ-selective inhibitors, recently approved for the treatment of human B-cell malignancies, therefore, present a new therapeutic opportunity to prevent the restenosis upon artery injury. Portland Press Ltd. 2017-09-28 /pmc/articles/PMC5617917/ /pubmed/28851839 http://dx.doi.org/10.1042/BSR20171112 Text en © 2017 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
Bilancio, Antonio
Rinaldi, Barbara
Oliviero, Maria Antonietta
Donniacuo, Maria
Monti, Maria Gaia
Boscaino, Amedeo
Marino, Irene
Friedman, Lori
Rossi, Francesco
Vanhaesebroeck, Bart
Migliaccio, Antimo
Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury
title Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury
title_full Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury
title_fullStr Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury
title_full_unstemmed Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury
title_short Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury
title_sort inhibition of p110δ pi3k prevents inflammatory response and restenosis after artery injury
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617917/
https://www.ncbi.nlm.nih.gov/pubmed/28851839
http://dx.doi.org/10.1042/BSR20171112
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