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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carotid Artery Injuries / drug therapy
  • Carotid Artery Injuries / enzymology
  • Carotid Artery Injuries / immunology
  • Class Ib Phosphatidylinositol 3-Kinase / deficiency
  • Class Ib Phosphatidylinositol 3-Kinase / genetics
  • Enzyme Inhibitors / pharmacology
  • Femoral Artery / enzymology
  • Femoral Artery / immunology
  • Femoral Artery / injuries
  • Gene Targeting
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neointima / drug therapy
  • Neointima / enzymology*
  • Neointima / immunology*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Th1 Cells / drug effects*
  • Th1 Cells / immunology*
  • Thiazolidinediones / pharmacology


  • 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
  • Enzyme Inhibitors
  • Inflammation Mediators
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinoxalines
  • Thiazolidinediones
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, rat
  • Pik3cg protein, mouse