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

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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.