Narita Hiroshi, Chen Sen, Komori Kimihiro, Kadomatsu Kenji
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
J Vasc Surg. 2008 Jun;47(6):1322-9. doi: 10.1016/j.jvs.2007.12.037. Epub 2008 Mar 19.
Neointimal hyperplasia is strikingly suppressed in an endothelium injury model in mice deficient in the growth factor midkine. Knockdown of midkine expression by means of antisense oligonucleotide or small interfering RNA has been shown to lead to suppression of neointimal hyperplasia in a balloon injury model and a rabbit vein graft model; therefore, midkine is an essential factor for neointimal hyperplasia. These findings, however, do not necessarily apply to the function of midkine in vascular stenoses such as in-stent restenosis, because human vascular stenosis is often accompanied by atherosclerosis.
We investigated midkine expression in the neointima induced by implantation of a bare metal stent in the atheromatous lesions of hypercholesterolemic rabbits. We analyzed midkine expression during a THP-1 cell differentiation and in peritoneal macrophages exposed to low-density lipoprotein or oxidized low-density lipoprotein.
Midkine expression reached the maximum level within 7 days after stenting and was detected in infiltrating macrophages. Differentiation of THP-1 cells to macrophage-like cells did not trigger midkine expression. Neither low-density lipoprotein nor oxidized low-density lipoprotein enhanced midkine expression in peritoneal macrophages that had been activated by thioglycollate, although these cells expressed a significant amount of midkine.
The results indicate that macrophages are the major source of midkine in the atherosclerotic neointima. The amount of midkine expressed in macrophages may be sufficient (ie, further enhancement of the expression is not necessary) for the pathogenesis, because oxidized low-density lipoprotein stimulation did not induce the midkine expression.
The growth factor midkine is induced during vascular stenosis in mouse and rat models with normal diet. Knockdown of midkine expression suppresses neointimal hyperplasia. The vascular response after stenting differs from that after balloon injury in that the inflammation is more prolonged and the accumulation of macrophages is more abundant in stent-injured vessel. We found here that macrophages are the major source of midkine in the atherosclerotic neointima of in-stent restenosis in hypercholesterolemic rabbits. Our data suggest that midkine has an important role in in-stent restenosis of atherosclerotic vessels and is a candidate molecular target to prevent in-stent restenosis.
在生长因子中期因子缺乏的小鼠内皮损伤模型中，新生内膜增生受到显著抑制。通过反义寡核苷酸或小干扰RNA敲低中期因子表达已被证明可导致在球囊损伤模型和兔静脉移植模型中新生内膜增生受到抑制；因此，中期因子是新生内膜增生的一个重要因素。然而，这些发现不一定适用于中期因子在血管狭窄（如支架内再狭窄）中的作用，因为人类血管狭窄常伴有动脉粥样硬化。
我们研究了在高胆固醇血症兔的动脉粥样硬化病变中植入裸金属支架后新生内膜中中期因子的表达。我们分析了THP-1细胞分化过程中以及暴露于低密度脂蛋白或氧化低密度脂蛋白的腹腔巨噬细胞中中期因子的表达。
中期因子表达在支架置入后7天内达到最高水平，并在浸润的巨噬细胞中检测到。THP-1细胞向巨噬细胞样细胞的分化未引发中期因子表达。尽管这些细胞表达大量中期因子，但低密度脂蛋白和氧化低密度脂蛋白均未增强经巯基乙酸激活的腹腔巨噬细胞中的中期因子表达。
结果表明巨噬细胞是动脉粥样硬化新生内膜中中期因子的主要来源。巨噬细胞中表达的中期因子量对于发病机制可能已足够（即无需进一步增强表达），因为氧化低密度脂蛋白刺激未诱导中期因子表达。
在正常饮食的小鼠和大鼠模型中，血管狭窄期间诱导生长因子中期因子。敲低中期因子表达可抑制新生内膜增生。支架置入后的血管反应与球囊损伤后的不同，在于支架损伤血管中的炎症持续时间更长且巨噬细胞积累更丰富。我们在此发现巨噬细胞是高胆固醇血症兔支架内再狭窄动脉粥样硬化新生内膜中中期因子的主要来源。我们的数据表明中期因子在动脉粥样硬化血管的支架内再狭窄中起重要作用，并且是预防支架内再狭窄的候选分子靶点。
