Peroxisome proliferator-activated receptor γ ligands inhibit retinoblastoma phosphorylation and G1 → S transition in vascular smooth muscle cells

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily that is activated by binding certain fatty acids, eicosanoids, and insulin-sensitizing thiazolidinediones (TZD). The TZD troglitazone (TRO) inhibits vascular smooth muscle cell proliferation and migration both in vitro and in vivo. The precise mechanism of its antiproliferative activity, however, has not been elucidated. We report here that PPARγ ligands inhibit rat aortic vascular smooth muscle cell proliferation by blocking the events critical for G1 → S progression. Flow cytometry demonstrated that both TRO and another TZD, rosiglitazone, prevented G1 → S progression induced by platelet-derived growth factor and insulin. Movement of cells from G1 → S was also inhibited by the non-TZD, natural PPARγ ligand 15-deoxy-12,14 Δ prostaglandin J2 (15d-PGJ2), and the mitogen-activated protein kinase pathway inhibitor PD98059. Inhibition of G1 → S exit by these compounds was accompanied by a substantial blockade of retinoblastoma protein phosphorylation. TRO and rosiglitazone attenuated both the mitogen-induced degradation of p27(kip1) and the mitogenic induction of p21(cip1). 15d-PGJ2 and PD98059 inhibited both the degradation of p27(kip1) and the induction of cyclin D1 in response to mitogens. These effects resulted in the inhibition of mitogenic stimulation of cyclin-dependent kinases activated by cyclins D1 and E. These data demonstrate that PPARγ ligands are antiproliferative drugs that act by modulating cyclin-dependent kinase inhibitors; they may provide a new therapeutic approach for proliferative vascular diseases.