Dexamethasone inhibits vascular smooth muscle cell migration via modulation of matrix metalloproteinase activity.
BACKGROUND
Dexamethasone (DEX) has been shown to inhibit development of neointimal hyperplasia in rats. We hypothesize that DEX inhibits neointimal hyperplasia by altering matrix metalloproteinase (MMP) activity, resulting in inhibition of smooth muscle cell migration.


METHODS
Rat aortic smooth muscle cells (RASMC) were harvested and cultured for two to four passages. A migration assay was performed in a Boyden chamber with chemoattractant (platelet-derived growth factor) and varying concentrations of DEX (10(-9) to 10(-5) M). The number of migrated cells was counted under light microscopy. Zymography was performed on culture media to assess MMP activity, and Western blotting was performed to assay MMP and levels of tissue inhibitors of MMPs (TIMPs).


RESULTS
DEX progressively inhibited RASMC migration in a dose-dependent fashion. This effect was statistically significant for concentrations of 10(-7) to 10(-5) M (P < 0.0005). Zymography showed that DEX inhibits MMP-2 activity in a dose-dependent manner. Western blots indicated that total MMP-2 secretion was inhibited and that TIMP-2 secretion was increased by DEX.


CONCLUSIONS
DEX inhibits platelet-derived growth factor-induced migration of RASMCs and MMP-2 activity in vitro. Our data suggest that DEX suppresses MMP activity and secretion, resulting in the inhibition of smooth muscle cell migration. This may explain the mechanism by which DEX inhibits neointimal hyperplasia.
Pross
C
C
Division of Vascular Surgery, University of California-Los Angeles Medical Center, Los Angeles, California 90096, USA.
Farooq
M M
MM
Angle
N
N
Lane
J S
JS
Cerveira
J J
JJ
Xavier
A E
AE
Freischlag
J A
JA
Law
R E
RE
Gelabert
H A
HA
D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D005938:Glucocorticoids; D019716:Tissue Inhibitor of Metalloproteinase-2; D003907:Dexamethasone; D020778:Matrix Metalloproteinase 2