RT Journal Article
SR Electronic
T1 15-Deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub>Induces G<sub>1</sub> Arrest and Differentiation Marker Expression in Vascular Smooth Muscle Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 837
OP 844
DO 10.1124/mol.58.4.837
VO 58
IS 4
A1 Yoshikazu Miwa
A1 Toshiyuki Sasaguri
A1 Hiroyasu Inoue
A1 Yoji Taba
A1 Akio Ishida
A1 Takeo Abumiya
YR 2000
UL http://molpharm.aspetjournals.org/content/58/4/837.abstract
AB In search of substances useful for the treatment of atherosclerotic vascular diseases, we studied the effects of 15-deoxy-Δ12,14-prostaglandin J2(15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor γ, on the proliferation and differentiation of vascular smooth muscle cells (VSMCs). 15d-PGJ2 but not WY14643, an agonist for peroxisome proliferator-activated receptor α, dose-dependently inhibited VSMC proliferation; the effect was maximal at 12 μM. 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-PGJ2was 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-PGJ2. A long-term treatment of exponentially growing VSMCs with 15d-PGJ2 markedly elevated the mRNA level of SM1 and, moreover, induced SM2, another isoform expressed exclusively in mature VSMCs. 15d-PGJ2 also increased the expression levels of calponin-h1 and smooth muscle α-actin. These results suggest that 15d-PGJ2 induces G1 arrest by two distinct mechanisms and promotes VSMC differentiation.