Abstract
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.
Footnotes
- Received January 27, 2000.
- Accepted June 27, 2000.
-
Send reprint requests to: Toshiyuki Sasaguri, M.D., Ph.D., Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail:sasaguri{at}ri.ncvc.go.jp
-
This study was supported in part by grants from the Ministry of Health and Welfare (Research Grants for Cardiovascular Diseases 9A-4 and 11C-1), the Ministry of Education, Science, and Culture (a Grant-in-Aid for Scientific Research), Science and Technology Agency [Special Coordination Funds for Promoting Science and Technology (Encouragement System of Center of Excellence)], Japan Cardiovascular Research Foundation, and Sankyo Foundation of Life Science.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|