Trichostatin A, an inhibitor of histone deacetylase, inhibits smooth muscle cell proliferation via induction of p21(WAF1).
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 (TSA), a specific and potent HDAC inhibitor, on the proliferation of vascular smooth muscle cells (VSMCs) isolated from rat thoracic aorta. TSA 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, TSA reduced the phosphorylation of Rb protein, a regulator of cell-cycle progression. TSA treatment also induced the expression of p21(WAF1) but not of p16(INK4), p27(KIP1) or p53. Finally, TSA inhibited HDAC activity of VSMCs from p21(WAF1) knock-out mice but had no effect on VSMC proliferation in these animals. In conclusion, TSA 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.
Okamoto
Hiroshi
H
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Fujioka
Yoshio
Y
Takahashi
Akihiro
A
Takahashi
Tomosaburo
T
Taniguchi
Takahiro
T
Ishikawa
Yuichi
Y
Yokoyama
Mitsuhiro
M
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D013936:Thymidine / Q000378:metabolism
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011500:Protein Synthesis Inhibitors; C012589:trichostatin A; D013936:Thymidine