BubR1 insufficiency inhibits neointimal hyperplasia through impaired vascular smooth muscle cell proliferation in mice
BubR1 insufficiency inhibits neointimal hyperplasia through impaired vascular smooth muscle cell proliferation in mice
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BubR1 不足通过小鼠血管平滑肌细胞增殖受损抑制新生内膜增生
DOI：
10.1161/atvbaha.114.304737
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Y.
中科院分区：
文献类型：
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作者：
Kyuragi;R.;Matsumoto;T.;Harada;Y.;Saito;S.;Onimaru;M.;Nakatsu;Y.;Tsuzuki;T.;Nomura;M.;Yonemitsu;Y.;Maehara;Y.
BubR 1是一种细胞周期相关蛋白，是调节细胞分裂的纺锤体检查点的重要组成部分。BubR 1表达降低到正常水平的10%的小鼠显示出以早衰为特征的表型;然而，BubR 1参与血管疾病仍然是未知的。我们产生的小鼠中，BubR 1的表达减少到20%（BubR 1 L/L小鼠），在野生型小鼠（BubR 1 +/+）调查的影响BubR 1动脉内膜hyperplasia.Approach and Results 10周龄的maleBubR 1 L/土地年龄匹配的野生型同窝仔（BubR 1 +/+）在这项研究中使用。结扎左侧颈总动脉，4周后行组织病理学检查。还进行了骨髓移植。从胸主动脉分离血管平滑肌细胞（VSMCs），以检查细胞增殖、迁移和细胞周期进展。在BubR 1 +/+小鼠中观察到动脉结扎后严重的新生内膜增生，而BubR 1 L/L小鼠显示几乎完全抑制新生内膜增生。所有供者骨髓移植均不影响3种造血细胞系的重建，BubR 1 +/+小鼠骨髓移植至BubR 1 L/L小鼠后，新生内膜增生仍受到抑制。BubR 1 L/L小鼠VSMC增殖受抑，进入S期延迟。VSMC迁移在这些BubR 1 L/L小鼠中不受影响。p38丝裂原活化蛋白激酶抑制VSMCs表达BubR 1，而BubR 1抑制VSMCs表达p38。结论BubR 1可能是治疗血管成形术后再狭窄等血管重塑病理状态的新靶分子。
ObjectiveBubR1, a cell cycle–related protein, is an essential component of the spindle checkpoint that regulates cell division. Mice with BubR1 expression reduced to 10% of the normal level display a phenotype characterized by progeria; however, the involvement of BubR1 in vascular diseases is still unknown. We generated mice in which BubR1 expression was reduced to 20% (BubR1L/Lmice) of that in wild-type mice (BubR1+/+) to investigate the effects of BubR1 on arterial intimal hyperplasia.Approach and ResultsTen-week-old maleBubR1L/Land age-matched wild-type littermates (BubR1+/+) were used in this study. The left common carotid artery was ligated, and histopathologic examinations were conducted 4 weeks later. Bone marrow transplantation was also performed. Vascular smooth muscle cells (VSMCs) were isolated from the thoracic aorta to examine cell proliferation, migration, and cell cycle progression. Severe neointimal hyperplasia was observed after artery ligation inBubR1+/+mice, whereasBubR1L/Lmice displayed nearly complete inhibition of neointimal hyperplasia. Bone marrow transplantation from all donors did not affect the reconstitution of 3 hematopoietic lineages, and neointimal hyperplasia was still suppressed after bone marrow transplantation fromBubR1+/+mice toBubR1L/Lmice. VSMC proliferation was impaired inBubR1L/Lmice because of delayed entry into the S phase. VSMC migration was unaffected in theseBubR1L/Lmice. p38 mitogen–activated protein kinase–inhibited VSMCs showed low expression of BubR1, and BubR1-inhibited VSMCs showed low expression of p38.ConclusionsBubR1 may represent a new target molecule for treating pathological states of vascular remodeling, such as restenosis after angioplasty.