Peroxisome proliferator-activated receptor gamma ligands inhibit retinoblastoma phosphorylation and G(1) -> S transition in vascular smooth muscle cells

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member o f the nuclear receptor superfamily that is activated by binding certain fat ty acids, eicosanoids, and insulin-sensitizing thiazolidinediones (TZD). Th e TZD troglitazone (TRO) inhibits vascular smooth muscle cell proliferation and migration both in vitro and in vivo, The precise mechanism of its anti proliferative activity, however, has not been elucidated. We report here th at PPAR gamma ligands inhibit rat aortic vascular smooth muscle cell prolif eration by blocking the events critical for G(1) --> S progression. Flow cy tometry demonstrated that both TRO and another TZD, rosiglitazone, prevente d G(1) --> S progression induced by platelet-derived growth factor and insu lin. Movement of cells from G(1) --> S was also inhibited by the non-TZD, n atural PPAR gamma ligand 15-deoxy-(12,14)Delta prostaglandin J(2) (15d-PGJ( 2)), and the mitogen-activated protein kinase pathway inhibitor PD98059. In hibition of G(1) --> S exit by these compounds was accompanied by a substan tial blockade of retinoblastoma protein phosphorylation, TRO and rosiglitaz one attenuated both the mitogen-induced degradation of p27(kip1) and the mi togenic induction of p21(cip1). 15d-PGJ(2) and PD98059 inhibited both the d egradation of p27(kip1) and the induction of cyclin D1 in response to mitog ens. These effects resulted in the inhibition of mitogenic stimulation of c yclin-dependent kinases activated by cyclins D1 and E. These data demonstra te that PPAR gamma ligands are antiproliferative drugs that act by modulati ng cyclin-dependent kinase inhibitors; they may provide a new therapeutic a pproach for proliferative vascular diseases.