title: 15-Deoxy-Delta(12,14)-prostaglandin J(2) induces G(1) arrest and differentiation marker expression in vascular smooth muscle cells.
abstract: In search of substances useful for the treatment of atherosclerotic vascular diseases, we studied the effects of 15-deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated receptor gamma, on the proliferation and differentiation of vascular smooth muscle cells (VSMCs). 15d-PGJ(2) but not WY14643, an agonist for peroxisome proliferator-activated receptor alpha, dose-dependently inhibited VSMC proliferation; the effect was maximal at 12 microM. 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 p21(Cip1/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 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 expression levels of calponin-h1 and smooth muscle alpha-actin. These results suggest that 15d-PGJ(2) induces G(1) arrest by two distinct mechanisms and promotes VSMC differentiation.
authors.affiliation: Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Miwa
authors.forename: T
authors.initials: T
authors.lastname: Sasaguri
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: Y
authors.initials: Y
authors.lastname: Taba
authors.forename: A
authors.initials: A
authors.lastname: Ishida
authors.forename: T
authors.initials: T
authors.lastname: Abumiya
mesh_terms: D000943:Antigens, Differentiation / Q000096:biosynthesis*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000096:biosynthesis; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000943:Antigens, Differentiation; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases; D016213:Cyclins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015230:Prostaglandin D2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C493956:CDKN1A protein, human