In search of substances useful for the treatment of atherosclerotic vascular diseases, we studied the effects of 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), a natural ligand for peroxisome proliferator-activated receptor ␥, on the proliferation and differentiation of vascular smooth muscle cells (VSMCs). 15d-PGJ 2 but not WY14643, an agonist for peroxisome proliferatoractivated receptor ␣, dose-dependently inhibited VSMC proliferation; the effect was maximal at 12 M. This compound strongly suppressed the activities of cyclin-dependent kinases (Cdk) 4, 6, and 2, thereby preventing the phosphorylation of the retinoblastoma protein. These Cdks seemed to be inhibited through two mechanisms: the down-regulation of cyclin D1 and the up-regulation of Cdk inhibitor p21Cip1/Waf1/Sdi1 . 15d-PGJ 2 was found to inhibit the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which mediates cyclin D1 expression. Mitogenic stimulation of quiescent cells decreased the level of mRNA for the smooth muscle-specific myosin heavychain SM1, whereas this reduction was prevented by 15d-PGJ 2 . A long-term treatment of exponentially growing VSMCs with 15d-PGJ 2 markedly elevated the mRNA level of SM1 and, moreover, induced SM2, another isoform expressed exclusively in mature VSMCs. 15d-PGJ 2 also increased the expression levels of calponin-h1 and smooth muscle ␣-actin. These results suggest that 15d-PGJ 2 induces G 1 arrest by two distinct mechanisms and promotes VSMC differentiation.Vascular smooth muscle cells (VSMCs) in the arterial media are fully differentiated to play their physiological roles as regulators of vascular wall tension. However, in atherosclerotic and restenotic lesions, their phenotypes have been converted to dedifferentiated (immature) ones (Owens, 1995). Dedifferentiated VSMCs migrate into the intima, proliferate, and synthesize extracellular matrices, thereby contributing to the formation of neointima. Therefore, to prevent VSMC hyperplasia in vivo, substances capable of promoting the differentiation of VSMCs may be more effective than those that simply inhibit their proliferation. A number of substances have been reported to inhibit VSMC proliferation, but few are also able to prevent phenotype conversion and induce differentiation.Prostaglandins (PGs) of the J 2 family, including PGJ 2 , ⌬ 12 -PGJ 2 , and 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), are naturally occurring metabolites of PGD 2 (Kikawa et al., 1984). We previously reported that PGJ 2 and ⌬
12-PGJ 2 strongly inhibit VSMC proliferation, although the underlying mechanisms remain undetermined (Sasaguri et al., 1992). Recently, PGs of the J 2 family were found to be natural ligands for peroxisome proliferator-activated receptor (PPAR) ␥, a member of the ligand-activated transcription factor nuclear receptor superfamily that includes receptors for steroid, retinoid, and thyroid hormones (Forman et al., 1995;Kliewer et al., 1995). PPAR␥ has been implicated in the induction of differentiation in adipocytes (Forman et al.,...