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J Exp Med. 2014 Aug 25;211(9):1779-92. doi: 10.1084/jem.20131276. Epub 2014 Jul 29.

Targeting PI3Kγ activity decreases vascular trauma-induced intimal hyperplasia through modulation of the Th1 response.

Author information

1
INSERM, UMR1048, F-31300 Toulouse, France Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, F-31300 Toulouse, France.
2
INSERM, UMR1048, F-31300 Toulouse, France Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, F-31300 Toulouse, France muriel.laffargue@inserm.fr stephanie.gayral@inserm.fr.
3
INSERM, UMR1043, F-31300 Toulouse, France UMR CNRS, U5282, F-31300 Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), F-31300 Toulouse, France.
4
INSERM, UMR1087, F-44007 Nantes, France CNRS 6291, F-44007 Nantes, France.
5
Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, F-31300 Toulouse, France CMEAB, F-31000 Toulouse, France.
6
Institute of Biochemistry and Genetics, University of Basel, 4058 Basel, Switzerland.
7
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy.
8
INSERM U1034, F-33600 Pessac, France.

Abstract

Interventional strategies to treat atherosclerosis, such as transluminal angioplasty and stent implantation, often cause vascular injury. This leads to intimal hyperplasia (IH) formation that induces inflammatory and fibroproliferative processes and ultimately restenosis. We show that phosphoinositide 3-kinase γ (PI3Kγ) is a key player in IH formation and is a valid therapeutic target in its prevention/treatment. PI3Kγ-deficient mice and mice expressing catalytically inactive PI3Kγ (PI3Kγ KD) showed reduced arterial occlusion and accumulation of monocytes and T cells around sites of vascular lesion. The transfer of PI3Kγ KD CD4(+) T cells into Rag2-deficient mice greatly reduced vascular occlusion compared with WT cells, clearly demonstrating the involvement of PI3Kγ in CD4(+) T cells during IH formation. In addition we found that IH is associated with increased levels of Th1 and Th17 cytokines. A specific decrease in the Th1 response was observed in the absence of PI3Kγ activity, leading to decreased CXCL10 and RANTES production by smooth muscle cells. Finally, we show that treatment with the PI3Kγ inhibitor AS-605240 is sufficient to decrease IH in both mouse and rat models, reinforcing the therapeutic potential of PI3Kγ inhibition. Altogether, these findings demonstrate a new role for PI3Kγ activity in Th1-controlled IH development.

PMID:
25073791
PMCID:
PMC4144742
DOI:
10.1084/jem.20131276
[Indexed for MEDLINE]
Free PMC Article

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