Rat and human aortic smooth muscle cells display differing migration and matrix metalloproteinase activities in response to dexamethasone.
OBJECTIVE
The steroid dexamethasone inhibits neointimal hyperplasia development in rats but not in humans. This study investigates the differential effects of dexamethasone on rat and human smooth muscle cell migration and matrix metalloproteinase (MMP) activity.


METHODS
Rat aortic smooth muscle cells were harvested from Sprague-Dawley rats. Human aortic smooth muscle cells were obtained from Clonetics. Boyden chamber migration assays were performed with chemoattractant (platelet-derived growth factor) and varying concentrations of dexamethasone (10(-9) to 10(-5) mol/L). Zymography of culture media was used to assess MMP activity, and Western blot analysis was used for quantification of MMP-2 and tissue inhibitor of MMP-2 (TIMP-2) secretion.


RESULTS
Dexamethasone inhibits rat aortic smooth muscle cell migration in a dose-dependent fashion. An increase in concentrations of dexamethasone does not effect human aortic smooth muscle cell migration. Rat aortic smooth muscle cell MMP-2 activity is inhibited with dexamethasone in a dose-dependent fashion, and human aortic smooth muscle cell MMP-2 activity is unchanged with dexamethasone. MMP-2 secretion is inhibited with dexamethasone in rat aortic smooth muscle cells but remains unaltered in human aortic smooth muscle cells. Dexamethasone increases rat aortic smooth muscle cell TIMP-2 secretion, and human aortic smooth muscle cell TIMP-2 secretion remains constant.


CONCLUSIONS
Dexamethasone inhibits rat aortic smooth muscle cell migration, MMP-2 activity, and MMP-2 secretion and increases TIMP-2 secretion. These effects are not observed in human aortic smooth muscle cells. These findings may explain why dexamethasone inhibits neointimal hyperplasia in animal models but is ineffective in humans. Inhibition of human smooth muscle cell migration in vitro may be useful in predicting the effectiveness of future therapeutic agents for treatment of neointimal hyperplasia in humans.
Pross
C
C
Division of Vascular Surgery, Gonda (Goldschmied) Center for Vascular Surgery, University of California-Los Angeles Medical Center, UCLA School of Medicine, 200 Medical Plaza, Los Angeles, CA 90095, USA.
Farooq
M M
MM
Lane
J S
JS
Angle
N
N
Tomono
C K
CK
Xavier
A E
AE
Freischlag
J A
JA
Collins
A E
AE
Law
R E
RE
Gelabert
H A
HA
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D006965:Hyperplasia; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D017539:Tunica Intima
D019716:Tissue Inhibitor of Metalloproteinase-2; D003907:Dexamethasone; D020778:Matrix Metalloproteinase 2