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

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.