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Vol. 58, Issue 4, 837-844, October 2000

15-Deoxy-Delta 12,14-prostaglandin J2 Induces G1 Arrest and Differentiation Marker Expression in Vascular Smooth Muscle Cells

Yoshikazu Miwa, Toshiyuki Sasaguri, Hiroyasu Inoue, Yoji Taba, Akio Ishida, and Takeo Abumiya

Departments of Bioscience (Y.M., T.S., Y.T., A.I.), Pharmacology (H.I.), and Epidemiology (T.A.), National Cardiovascular Center Research Institute, Osaka, Japan; Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka (Y.M.); and Third Department of Internal Medicine, University of the Ryukyus School of Medicine, Okinawa, Japan (Y.T., A.I.)

In search of substances useful for the treatment of atherosclerotic vascular diseases, we studied the effects of 15-deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor gamma , on the proliferation and differentiation of vascular smooth muscle cells (VSMCs). 15d-PGJ2 but not WY14643, an agonist for peroxisome proliferator-activated receptor alpha , 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-PGJ2 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-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 alpha -actin. These results suggest that 15d-PGJ2 induces G1 arrest by two distinct mechanisms and promotes VSMC differentiation.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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