15-deoxy-Delta(12,14)-prostaglandin J(2) induces G(1) arrest and differentiation marker expression in vascular smooth muscle cells

In search of substances useful for the treatment of atherosclerotic vascula r diseases, we studied the effects of 15-deoxy-(12,14)-prostaglandin J(2) ( 15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated recepto r gamma, on the proliferation and differentiation of vascular smooth muscle cells (VSMCs). 15d-PGJ(2) but not WY14643, an agonist for peroxisome proli ferator-activated receptor alpha, dose-dependently inhibited VSMC prolifera tion; the effect was maximal at 12 mu M. This compound strongly suppressed the activities of cyclin-dependent kinases (Cdk) 4, 6, and 2, thereby preve nting the phosphorylation of the retinoblastoma protein. These Cdks seemed to be inhibited through two mechanisms: the down-regulation of cyclin D1 an d the up-regulation of Cdk inhibitor p21(Cip1/Waf1/Sdi1). 15d-PGJ(2) was fo und to inhibit the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which mediates cyclin D1 expression. Mitogenic stimulation of qui escent cells decreased the level of mRNA for the smooth muscle-specific myo sin heavy-chain 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 expre ssion levels of calponin-h1 and smooth muscle alpha-actin. These results su ggest that 15d-PGJ(2) induces G(1) arrest by two distinct mechanisms and pr omotes VSMC differentiation.