Trichostatin A, an Inhibitor of Histone Deacetylase, Inhibits Smooth Muscle Cell Proliferation via Induction of p21WAF1

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  • Okamoto Hiroshi
    Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine
  • Fujioka Yoshio
    Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine Laboratory of Nutritional Physiology, Faculty of Nutrition, Kobegakuin University
  • Takahashi Akihiro
    Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine
  • Takahashi Tomosaburo
    Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine
  • Taniguchi Takahiro
    Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine
  • Ishikawa Yuichi
    Faculty of Health Sciences, Kobe University School of Medicine
  • Yokoyama Mitsuhiro
    Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine

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説明

The proliferation of vascular smooth muscle cells (VSMCs) can contribute to a variety of pathological states, including atherosclerosis and post-angioplasty restenosis. The p21WAF1 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 p21WAF1. 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 p21WAF1 but not of p16INK4, p27KIP1 or p53. Finally, TSA inhibited HDAC activity of VSMCs from p21WAF1 knock-out mice but had no effect on VSMC proliferation in these animals. In conclusion, TSA inhibits VSMC proliferation via the induction of p21WAF1 expression and subsequent cell-cycle arrest with reduction of the phosphorylation of Rb protein at the G1-S phase.

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