Development of therapeutic methods for arterial restenosis : intraarterial radiation, pharmaceutical approach and gene therapy

本研究的目的是开发多种方法来预防动脉再狭窄，即低剂量放射性支架发射β粒子，药物方法和基因治疗。我们首先在日本原子能研究所的TIARA（用于高级辐射应用的高崎离子加速器）设施中将133-氚离子植入带有同位素分离器的管状开槽不锈钢支架中。所生产的支架具有均匀的放射性分布和1.60*0.81 μ Ci的活性水平。放射性支架可有效防止新生内膜形成。植入兔主动脉后28天，与对照支架相比，β-粒子发射支架的新生内膜面积与中膜面积比显著降低（放射性支架为0.43 *0.15，对照支架为0.61*0.18，p=0.05）。由于半衰期短，无法进口，因此在日本开发β粒子发射支架非常重要。关于引起平滑肌表型调节的因素，我们已经确定锌指蛋白BTEB 2是非肌肌球蛋白重链（SMemb）基因的转录因子。BTEB 2还激活了许多血管疾病相关基因，如组织因子、PAL-1、Egr-1基因。BTEB 2基因受早期反应基因Egr- 1通过MEK 1调控。这些结果表明BTEB 2作为一种转录因子参与了血管平滑肌细胞的表型调节。以BTEB 2为分子标记，我们发现维甲酸和普罗布考对巨噬细胞和平滑肌细胞都有失活作用。

The objective of this study was to develop multiple approaches to prevent arterial restenosis, that is low-dose radioactive stents emitting beta-particle, pharmaceutical methods and gene therapy. We first implanted 133-Xe ions into tubular slotted stainless steel stents with the isotope separator installed at the TIARA (Takasaki Ion Accelerators for Advanced Radiation Application) facility at the Japan Atomic Energy Research Institute. The stents produced had homogeneous distribution of radioactivity and activity levels of 1.60*0.81 muCi. The radioactive stents were effective in preventing neointimal formation. Twenty-eight days after implantation in rabbit aorta, neointimal area was significantly reduced when to medial area ratio in the beta -particle emitting stents compared with control stents (0.43 *0.15 in radioactive stents versus 0.61*0.18 in control stents, p=0.05). Development of beta-particle emitting in Japan is important in that these stents cannot be imported because of short half-lives.Regarding factrors that cause smooth muscle phenotypic modulation, we have identified zinc finger protein BTEB2 as a transcription factor for nonmuscle myosin heavy chain (SMemb) gene. BTEB2 also activates a number of vascular disease-associated genes, such as tissue factor, PAL-1, Egr-1 gene. BTEB2 gene is regulated by Egr- 1, an early response gene, through MEK1. These results suggest that BTEB2 functions as a transcription factor for phenotypic modulation of vascular smooth muscle cells, By using BTEB2 as a molecular marker, we found that retinoic acid and probucol deactivate macrophages as well as smooth muscle cell.