Suzuki J, Isobe M, Morishita R, Aoki M, Horie S, Okubo Y, Kaneda Y, Sawa Y, Matsuda H, Ogihara T, Sekiguchi M
First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
Nat Med. 1997 Aug;3(8):900-3. doi: 10.1038/nm0897-900.
Graft coronary arteriosclerosis, which limits the long-term survival of allograft recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. We observed that messenger RNA of the cell cycle regulatory enzyme cyclin-dependent kinase (cdk) 2 kinase, which mediates smooth muscle cell proliferation, was elevated in the thickened intima of coronary arteries of murine heterotopic cardiac allografts. We studied the effects of antisense phosphorothioate oligodeoxynucleotide (ODN) against this enzyme using gene transfer mediated by a hemagglutinating virus of Japan (HVJ)-liposome complex intraluminally delivered to inhibit the intimal hyperplasia. At 30 days after transplantation, antisense cdk2 kinase ODN treatment had dramatically inhibited neointimal formation in the allografts. Expression of vascular cell adhesion molecule-1 was also suppressed by antisense cdk2 kinase. However, these effects were not observed in the sense or scrambled ODN-treated allografts. Thus, an intraluminal administration of antisense ODN directed to a specific cell cycle regulatory gene can inhibit neointimal formation after cardiac transplantation.
移植冠状动脉粥样硬化限制了同种异体移植受者的长期存活，其特征是由增殖性平滑肌细胞组成的弥漫性内膜增厚。我们观察到，介导平滑肌细胞增殖的细胞周期调节酶细胞周期蛋白依赖性激酶（cdk）2激酶的信使核糖核酸在小鼠异位心脏同种异体移植冠状动脉增厚的内膜中升高。我们使用由日本血凝病毒（HVJ）-脂质体复合物介导的基因转移在管腔内递送针对该酶的反义硫代磷酸酯寡脱氧核苷酸（ODN），以抑制内膜增生。移植后30天，反义cdk2激酶ODN治疗显著抑制了同种异体移植中的新生内膜形成。血管细胞黏附分子-1的表达也被反义cdk2激酶抑制。然而，在正义或随机ODN处理的同种异体移植中未观察到这些效果。因此，向特定细胞周期调节基因进行管腔内反义ODN给药可抑制心脏移植后的新生内膜形成。
