Dexamethasone suppresses vascular smooth muscle cell proliferation.
BACKGROUND
Experimental studies in vivo have demonstrated that dexamethasone inhibits neointimal hyperplasia following arterial injury. The mechanisms of this inhibition have not been clearly defined. Our objective was to test the hypothesis that dexamethasone directly suppresses smooth muscle cell (SMC) proliferation by inhibiting cell cycle progression and the expression of key cell cycle-dependent genes.


METHODS
Cultured rat aortic SMC were treated with incremental concentrations of dexamethasone and cell number was determined after 72 h. To determine if dexamethasone inhibited cell cycle progression, cells were synchronized, then restimulated to enter the cell cycle, and treated with or without dexamethasone. DNA synthesis was determined 24 h after restimulation by measuring [3H]thymidine incorporation. To define the point of action of dexamethasone in the cell cycle, synchronized SMC were treated with dexamethasone (10(-7) M) at various time points after entry into the cell cycle. Flow cytometry and Northern blots were performed to examine cell cycle progression and the expression of smooth muscle cell cycle-dependent genes c-fos, c-myc, and thymidine kinase (TK).


RESULTS
Dexamethasone treatment induced a concentration-dependent inhibition of SMC proliferation and DNA synthesis. The cell cycle progression of synchronized SMC from G1 into S phase was inhibited by dexamethasone, even when added as late as 16 h after restimulation. The expression of TK was suppressed by dexamethasone, while c-fos and c-myc were not affected.


CONCLUSIONS
Dexamethasone inhibits the proliferation of SMC in a concentration-dependent fashion. This inhibition is associated with a block in cell cycle progression late in G1 phase of the cell cycle. Consistent with this finding, dexamethasone does not alter the expression of the early cell cycle-dependent genes c-fos and c-myc, but significantly inhibits the expression of TK, a marker of late G1 phase.
Reil
T D
TD
UCLA School of Medicine, University of California at Los Angeles, Los Angeles, California, 90095, USA.
Sarkar
R
R
Kashyap
V S
VS
Sarkar
M
M
Gelabert
H A
HA
D000818:Animals; D001790:Blood Physiological Phenomena; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051381:Rats
D005938:Glucocorticoids; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D003907:Dexamethasone