title: Targeting PI3Kγ activity decreases vascular trauma-induced intimal hyperplasia through modulation of the Th1 response.
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.
authors: INSERM, UMR1048, F-31300 Toulouse, France Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, F-31300 Toulouse, France.
authors: Natalia F
authors: NF
authors: Smirnova
authors: 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.
authors: Stéphanie
authors: S
authors: Gayral
authors: 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.
authors: Christophe
authors: C
authors: Pedros
authors: INSERM, UMR1087, F-44007 Nantes, France CNRS 6291, F-44007 Nantes, France.
authors: Gervaise
authors: G
authors: Loirand
authors: INSERM, UMR1087, F-44007 Nantes, France CNRS 6291, F-44007 Nantes, France.
authors: Nathalie
authors: N
authors: Vaillant
authors: INSERM, UMR1048, F-31300 Toulouse, France Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, F-31300 Toulouse, France.
authors: Nicole
authors: N
authors: Malet
authors: 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.
authors: Sahar
authors: S
authors: Kassem
authors: INSERM, UMR1048, F-31300 Toulouse, France Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, F-31300 Toulouse, France.
authors: Denis
authors: D
authors: Calise
authors: Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, F-31300 Toulouse, France CMEAB, F-31000 Toulouse, France.
authors: Dominique
authors: D
authors: Goudounèche
authors: Institute of Biochemistry and Genetics, University of Basel, 4058 Basel, Switzerland.
authors: Matthias P
authors: MP
authors: Wymann
authors: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy.
authors: Emilio
authors: E
authors: Hirsch
authors: INSERM U1034, F-33600 Pessac, France.
authors: Alain-Pierre
authors: AP
authors: Gadeau
authors: INSERM, UMR1048, F-31300 Toulouse, France Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, F-31300 Toulouse, France.
authors: Laurent O
authors: LO
authors: Martinez
authors: 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.
authors: Abdelhadi
authors: A
authors: Saoudi
authors: 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.
authors: Muriel
authors: M
authors: Laffargue
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005263:Femoral Artery / Q000201:enzymology / Q000276:immunology / Q000293:injuries; D018390:Gene Targeting; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058426:Neointima / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology*; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546765:Pik3cg protein, rat; C546764:Pik3cg protein, mouse