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

Bilancio, A; Rinaldi, B; Oliviero, MA; Donniacuo, M; Monti, MG; Boscaino, A; Marino, I; ... Migliaccio, A; + view all (2017) Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury. Bioscience Reports , 37 (5) , Article BSR20171112. 10.1042/BSR20171112. Green open access

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Abstract

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 knock-in (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 to WT mice. Likewise, PI-3065, a p110δ-selective PI3K inhibitor, almost completely prevented restenosis after artery injury. Our data show that p110δ PI3K plays a main role in promoting neointimal thickening and inflammatory processes during vascular stenosis, with its inhibition providing significant reduction of 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.

Type: Article
Title: Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1042/BSR20171112
Publisher version: http://doi.org/10.1042/BSR20171112
Language: English
Additional information: Copyright © 2017 The Author(s). 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/).
Keywords: Phosphoinositide 3-kinase (PI3K), carotid, inflammatory cell, p110δ, restenosis
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/1573139
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