PPARdelta inhibits IL-1beta-stimulated proliferation and migration of vascular smooth muscle cells via up-regulation of IL-1Ra.
Activation of peroxisome proliferator-activated receptor (PPAR) delta by GW501516, a specific PPARdelta ligand, significantly inhibited interleukin (IL)-1beta-induced proliferation and migration of vascular smooth muscle cells (VSMCs). This effect of GW501516 was dependent on transforming growth factor-beta, and was mediated through the up-regulation of IL-1 receptor antagonist. The inhibitory effect of GW501516 on VSMC proliferation was associated with cell cycle arrest at the G1 to S phase transition, which was accompanied by the induction of p21 and p53 along with decreased cyclin-dependent kinase 4 expression. Inhibition of cell migration by GW501516 was associated with the down-regulation of matrix metalloproteinase (MMP)-2 and MMP-9 in IL-1beta-treated VSMCs. Inhibition of extracellular signal-regulated kinase significantly reduced the GW501516-mediated inhibition of IL-1beta-stimulated VSMC proliferation. These results suggest that PPARdelta plays an important role in the pathophysiology of diseases associated with the proliferation and migration of VSMCs.
Kim
H J
HJ
Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, 92 Chilam-Dong, Jinju, 660-751, Korea.
Kim
M Y
MY
Hwang
J S
JS
Kim
H J
HJ
Lee
J H
JH
Chang
K C
KC
Kim
J-H
JH
Han
C W
CW
Kim
J-H
JH
Seo
H G
HG
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D013844:Thiazoles; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000502:physiology*
C425931:GW 501516; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D047494:PPAR delta; D013844:Thiazoles; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9