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 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.
Miwa
Y
Y
Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan.
Sasaguri
T
T
Inoue
H
H
Taba
Y
Y
Ishida
A
A
Abumiya
T
T
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
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