Okamoto Hiroshi, Fujioka Yoshio, Takahashi Akihiro, Takahashi Tomosaburo, Taniguchi Takahiro, Ishikawa Yuichi, Yokoyama Mitsuhiro
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
J Atheroscler Thromb. 2006 Aug;13(4):183-91. doi: 10.5551/jat.13.183.
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.
血管平滑肌细胞（VSMC）的增殖会导致多种病理状态，包括动脉粥样硬化和血管成形术后再狭窄。p21（WAF1）细胞周期蛋白依赖性激酶抑制剂可调节受损血管中的细胞周期进程、衰老和分化。组蛋白脱乙酰酶（HDAC）抑制剂已显示出可控制多种肿瘤细胞系的增殖，可能是通过诱导p21（WAF1）的表达。我们的目标是研究曲古抑菌素A（TSA），一种特异性强效HDAC抑制剂，对从大鼠胸主动脉分离的血管平滑肌细胞（VSMC）增殖的影响。TSA以剂量依赖性方式抑制VSMC的HDAC活性，并通过细胞计数和[3H]胸苷掺入程度证明其抑制VSMC增殖。此外，TSA降低了细胞周期进程调节因子Rb蛋白的磷酸化。TSA处理还诱导了p21（WAF1）的表达，但未诱导p16（INK4）、p27（KIP1）或p53的表达。最后，TSA抑制了p21（WAF1）基因敲除小鼠VSMC的HDAC活性，但对这些动物的VSMC增殖没有影响。总之，TSA通过诱导p21（WAF1）表达以及随后在G1-S期减少Rb蛋白磷酸化导致细胞周期停滞来抑制VSMC增殖。
