Circulation, Vol 90, 2468-2473, Copyright © 1994 by American Heart Association
SJ Chen, YF Chen, DM Miller, H Li and S Oparil
BACKGROUND--Smooth muscle proliferation and extracellular matrix formation
in the subintimal region of blood vessels that have been subjected to
intimal injury are responsible for restenosis following balloon angioplasty
of the coronary arteries and for accelerated atherosclerosis in a variety
of other pathophysiological states. The immediate early-response gene c-myc
is overexpressed in proliferating vascular smooth muscle cells in vitro,
and c-myc antisense oligomers have been shown to reduce c-myc expression
and to inhibit proliferation of vascular smooth muscle cells in culture.
Mithramycin is a commercially available G-C-specific DNA binding drug that
selectively inhibits transcription of genes, such as c-myc, that have
G-C-rich promoter sequences. This study tested the hypothesis that
mithramycin inhibits transcription of the c-myc proto-oncogene and prevents
myointimal proliferation after balloon injury of the rat carotid artery in
vivo. METHODS AND RESULTS--Ten-week-old male Sprague-Dawley rats received
mithramycin (150 micrograms/kg IP) or distilled H2O 1 hour before and 1
hour after balloon injury of the right common carotid artery. After 2
weeks, the rats were killed by overdose of pentobarbital, and the injured
right and uninjured control left arteries were pressure-fixed and subjected
to morphological analysis for evaluation of the degree of myointimal
thickening. Separate groups of rats were killed at 2 and 6 hours after
vascular injury, and total RNA from injured and control vessels of
mithramycin- and vehicle- treated rats was subjected to Northern analysis
for assessment of steady-state c-myc mRNA levels. The areas of neointima
and the ratios of neointimal to medial area were significantly less in
mithramycin- treated than in control rats (0.6 +/- 0.1 versus 1.2 +/- 0.1
mm2, P < .01 and 95 +/- 16% versus 190 +/- 14%, P < .01). Lumen size
was significantly greater in mithramycin-treated than in control rats (1.5
+/- 0.1 versus 0.8 +/- 0.1 mm2, P < .01). Steady-state c-myc mRNA levels
were increased 10-fold and 2-fold (compared with undamaged carotid
arteries) at 2 and 6 hours after balloon injury, respectively; mithramycin
treatment reduced c-myc mRNA levels at 2 and 6 hours by 66% and 53%,
respectively. CONCLUSIONS--These results support the hypothesis that
systemic administration of mithramycin immediately (1 hour before and after
intervention effectively inhibits transcription of the c-myc proto-oncogene
and prevents myointimal proliferation after balloon injury of the rat
carotid artery in vivo. Because mithramycin has been shown to be well
tolerated by humans and to effectively inhibit transcription of c-myc in
proliferating human cells, this agent may be useful in the prevention of
coronary restenosis.
ARTICLES
Mithramycin inhibits myointimal proliferation after balloon injury of the rat carotid artery in vivo
Department of Medicine, University of Alabama at Birmingham.
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