Targeting PI3Kgamma activity decreases vascular trauma-induced intimal hyperplasia through modulation of the Th1 response

Smirnova, Natalia F. and Gayral, Stephanie and Pedros, Christophe and Loirand, Gervaise and Vaillant, Nathalie and Malet, Nicole and Kassem, Sahar and Calise, Denis and Goudouneche, Dominique and Wymann, Matthias P. and Hirsch, Emilio and Gadeau, Alain-Pierre and Martinez, Laurent O. and Saoudi, Abdelhadi and Laffargue, Muriel. (2014) Targeting PI3Kgamma activity decreases vascular trauma-induced intimal hyperplasia through modulation of the Th1 response. Journal of experimental medicine, 211 (9). pp. 1779-1792.

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Official URL: https://edoc.unibas.ch/62513/

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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 gamma (PI3Kgamma) is a key player in IH formation and is a valid therapeutic target in its prevention/treatment. PI3Kgamma-deficient mice and mice expressing catalytically inactive PI3Kgamma (PI3Kgamma KD) showed reduced arterial occlusion and accumulation of monocytes and T cells around sites of vascular lesion. The transfer of PI3Kgamma KD CD4(+) T cells into Rag2-deficient mice greatly reduced vascular occlusion compared with WT cells, clearly demonstrating the involvement of PI3Kgamma 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 PI3Kgamma activity, leading to decreased CXCL10 and RANTES production by smooth muscle cells. Finally, we show that treatment with the PI3Kgamma inhibitor AS-605240 is sufficient to decrease IH in both mouse and rat models, reinforcing the therapeutic potential of PI3Kgamma inhibition. Altogether, these findings demonstrate a new role for PI3Kgamma activity in Th1-controlled IH development.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Cancer- and Immunobiology (Wymann)
UniBasel Contributors:Wymann, Matthias P.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Rockefeller University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Aug 2020 12:55
Deposited On:04 Aug 2020 12:55

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