Department of Cardiovascular, Respiratory and Metabolic Medicine, Kagoshima University, Japan.
J Atheroscler Thromb. 2009;16(6):772-81. doi: 10.5551/jat.1917. Epub 2009 Dec 22.
Increased clusterin mRNA and protein levels have been detected in various tissues undergoing stress, and we previously reported that clusterin is markedly induced in media and neointima following vascular injury. The present study therefore investigated the impact of clusterin on neointimal hyperplasia following vascular injury.
As compared with wild-type mice, clusterin knockout mice (clusterin-KO) demonstrated a significant decrease of the intima/media ratio 4 weeks after cuff placement. Immunohistochemical analysis of injured femoral arteries in clusterin-KO demonstrated the accumulation of p53 in nuclei of neointimal vascular smooth muscle cells (VSMCs). Moreover, VSMCs from either clusterin-KO or rat VSMCs treated with clusterin-short-interfering (si) RNA subjected to static stretch exhibited significantly increased p53 and p21, and increased G1 cell cycle arrest as indicated by flow cytometry compared with VSMCs from wild-type mice.
Reduced clusterin expression reduced the proliferation of VSMCs and induced G1 arrest via p53 and p21. Clusterin therefore represents a promising molecular target to limit restenosis after coronary intervention.
在经历应激的各种组织中检测到聚集蛋白 mRNA 和蛋白水平增加，我们之前报道过，在血管损伤后，聚集蛋白在培养基和新生内膜中明显诱导。因此，本研究调查了聚集蛋白对血管损伤后新生内膜增生的影响。
与野生型小鼠相比，套管放置 4 周后，聚集蛋白敲除小鼠（clusterin-KO）的内膜/中膜比值显著降低。在 clusterin-KO 损伤的股动脉的免疫组织化学分析中，p53 在新生内膜血管平滑肌细胞（VSMCs）的核内积聚。此外，与来自野生型小鼠的 VSMCs 相比，来自 clusterin-KO 或用聚集蛋白小干扰（si）RNA 处理的大鼠 VSMCs 进行静态拉伸后，p53 和 p21 显著增加，并且如流式细胞术所示，G1 细胞周期停滞增加。
降低聚集蛋白的表达通过 p53 和 p21 减少 VSMCs 的增殖并诱导 G1 期阻滞。因此，聚集蛋白代表了限制冠状动脉介入治疗后再狭窄的有前途的分子靶标。
