Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury
Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury
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DOI：
10.1152/ajpheart.00555.2004
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发表时间：
2005-05-01
影响因子：
4.8
通讯作者：
Muramatsu, T
中科院分区：
文献类型：
--
作者：
Hayashi, K;Banno, H;Muramatsu, T
呼吸困难是血管成形术的主要临床问题。我们以前已经表明，新生内膜形成显着抑制中期因子（MK）缺陷小鼠。如果MK蛋白被给予缺陷小鼠，则新生内膜形成恢复。MK是一种肝素结合生长因子，参与炎症细胞和血管平滑肌细胞的迁移。因此，在缺陷小鼠中抑制新生内膜形成伴随着抑制炎性细胞募集到血管壁中。在这里，我们评估MK反义寡脱氧核苷酸（ODN）预防再狭窄的潜力。我们克隆了兔MK的cDNA，它在哺乳动物中显示出高度保守的序列。球囊损伤诱导MK表达，最高水平发生在血管成形术后7 - 14天，在兔颈动脉。两个反义寡核苷酸抑制MK在兔肾细胞系RK 13细胞中的产生，其中一个然后在球囊处理后立即通过脂质转染法转染到动脉壁中。反义ODN在体内抑制MK诱导，从而抑制新生内膜形成至对照水平的60%。这些结果表明MK是治疗血管再狭窄的候选分子靶点。
Restenosis is the major clinical problem of angioplasty. We have previously shown that neointima formation is strikingly suppressed in midkine (MK)- deficient mice. Neointima formation is restored if MK protein is administrated to the deficient mice. MK is a heparin- binding growth factor and implicated in the migration of inflammatory cells and vascular smooth muscle cells. Consistently, the suppression of neointima formation in the deficient mice is accompanied by suppression of recruitment of inflammatory cells into the vascular wall. Here, we evaluated the potential of MK antisense oligodeoxyribonucleotide (ODN) for the prevention of restenosis. We cloned the cDNA of rabbit MK, which showed a strongly conserved sequence in mammals. The balloon injury induced MK expression, with the maximum level occurring 7 - 14 days after angioplasty, in the rabbit carotid artery. Two antisense ODNs suppressed the production of MK in a rabbit kidney cell line, RK13 cells, one of which was then transfected into the arterial wall by means of lipofection immediately after balloon treatment. The antisense ODN suppressed MK induction in vivo and consequently suppressed neointima formation to 60% of the control level. These results suggest that MK is a candidate molecular target for the therapy for vascular restenosis.