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Okamoto H, Fujioka Y, Takahashi A, Takahashi T, Taniguchi T,
Ishikawa Y, Yokoyama M.
Trichostatin A, an Inhibitor of Histone Deacetylase,
Inhibits Smooth Muscle Cell Proliferation via Induction of
p21(WAF1).
J Atheroscler Thromb. 2006 Aug;13(4):183-91.
Division of Cardiovascular and Respiratory Medicine,
Department of Internal Medicine, Kobe University Graduate School
of Medicine, Kobe, Japan.
The proliferation of vascular smooth muscle cells (VSMCs) can
contribute to a variety of pathological states, including
atherosclerosis and post-angioplasty restenosis. The p21(WAF1)
cyclin-dependent kinase inhibitor regulates cell-cycle
progression, senescence, and differentiation in injured blood
vessels. Histone deacetylase (HDAC) inhibitors have shown
utility in controlling proliferation in a wide range of tumor
cell lines, possibly by inducing the expression of p21(WAF1).
Our goal was to investigate the effect of trichostatin A
(trichostatin A), a specific and potent HDAC inhibitor, on the
proliferation of vascular smooth muscle cells (VSMCs) isolated
from rat thoracic aorta. trichostatin A suppressed the HDAC
activity of VSMCs in a dose-dependent manner and inhibited VSMC
proliferation as demonstrated by cell number counting and the
degree of [3H] thymidine incorporation. Further, trichostatin A
reduced the phosphorylation of Rb protein, a regulator of
cell-cycle progression. trichostatin A treatment also induced
the expression of p21(WAF1) but not of p16(INK4), p27(KIP1) or
p53. Finally, trichostatin A inhibited HDAC activity of VSMCs
from p21(WAF1) knock-out mice but had no effect on VSMC
proliferation in these animals. In conclusion, trichostatin A
inhibits VSMC proliferation via the induction of p21(WAF1)
expression and subsequent cell-cycle arrest with reduction of
the phosphorylation of Rb protein at the G1-S phase.
PMID: 16908950
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