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

Antonio Bilancio,Irene Marino,Maria Gaia Monti,Lori Friedman,Maria Antonietta Oliviero,Antimo Migliaccio,Amedeo Boscaino,Bart Vanhaesebroeck,Francesco Rossi,Maria Donniacuo,Barbara Rinaldi

doi:10.1042/bsr20171112

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 knockin (KI) point mutation in its ATP-binding site (p110δD910A/D910A PI3K mice). Wild-type (WT) and p110δD910A/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.

Highlights

Restenosis is the pathophysiological process leading to the failure of revascularization procedures such as angioplasty and stenting in 10–15% of patients [1,2,3,4]
We investigated whether p110δ phosphoinositide 3-kinase (PI3K) inactivation protects against restenosis
We provide the first direct in vivo evidence, using both genetic and pharmacological approaches, that p110δ kinase activity contributes to immune cells migration to neointimal hyperplasia after carotid injury. p110δ PI3K belongs to a lipid kinase family which regulates multiple biological functions such as proliferation, migration, survival and growth [18,24,39,40]

Summary

Introduction

Restenosis is the pathophysiological process leading to the failure of revascularization procedures such as angioplasty and stenting in 10–15% of patients [1,2,3,4]. Vascular injury causes endothelial denudation and adhesion of activated platelets, which induce recruitment of inflammatory cells such as neutrophils, lymphocytes, monocytes and mast cells, promoting vascular smooth muscle cells (VSMCs) proliferation, migration and neointimal growth [5,6,7,8,9,10,11,12]. Several approaches such as artery stent placement, balloon angioplasty, drug-eluting coronary stents and gene therapy have been attempted to prevent the restenosis upon artery injury [13,14,15,16,17].

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Results

Conclusion