Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Cycle / genetics
-
Cell Cycle / physiology*
-
Cyclin-Dependent Kinase 4 / genetics
-
Cyclin-Dependent Kinase 4 / metabolism
-
Interleukin 1 Receptor Antagonist Protein / genetics
-
Interleukin 1 Receptor Antagonist Protein / metabolism
-
Interleukin-1 / genetics
-
Interleukin-1 / metabolism
-
Interleukin-1 / pharmacology
-
Interleukin-1beta / pharmacology
-
Matrix Metalloproteinase 9 / genetics
-
Matrix Metalloproteinase 9 / metabolism
-
Matrix Metalloproteinase 9 / pharmacology
-
Mitogen-Activated Protein Kinases / genetics
-
Mitogen-Activated Protein Kinases / metabolism
-
Mitogen-Activated Protein Kinases / pharmacology
-
Muscle, Smooth, Vascular / cytology
-
Muscle, Smooth, Vascular / drug effects
-
Muscle, Smooth, Vascular / metabolism*
-
Myocytes, Smooth Muscle / cytology
-
Myocytes, Smooth Muscle / drug effects
-
Myocytes, Smooth Muscle / metabolism*
-
PPAR delta / genetics
-
PPAR delta / metabolism
-
PPAR delta / physiology*
-
Rats
-
Thiazoles
-
Transcriptional Activation
-
Up-Regulation / physiology*
Substances
-
GW 501516
-
Interleukin 1 Receptor Antagonist Protein
-
Interleukin-1
-
Interleukin-1beta
-
PPAR delta
-
Thiazoles
-
Cdk4 protein, rat
-
Cyclin-Dependent Kinase 4
-
Mitogen-Activated Protein Kinases
-
Matrix Metalloproteinase 9