Phosphatidylinositol 3-Kinase Inhibitors Block Aortic Smooth Muscle Cell Proliferation in Mid-Late G1 Phase: Effect on Cyclin-Dependent Kinase 2 and the Inhibitory Protein p27KIP1☆

Abstract In the present study, we investigated the involvement of phosphatidylinositol 3-kinase (PI 3-kinase) activity in the progression of vascular smooth muscle cells (VSMCs) throughout the G1 phase of cell cycle. Addition of two selective inhibitors of PI 3-kinase, LY 294002 or wortmannin, to quiescent VSMCs prevented serum-induced DNA synthesis in a dose-dependent manner with IC50 of 8.7 ± 2.0 μM and 53.9 ± 8.5 nM, respectively. Time course studies revealed that the two PI 3-kinase inhibitors blocked VSMC proliferation in mid-late G1 phase, about 6 h before the G1/S transition. This G1 growth arrest was due, at least in part, to the reduction of the CDK2 associated kinase activity resulting mainly from the upregulation of the inhibitory protein p27 KIP1 .