Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model
Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model
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DOI：
10.1161/01.cir.0000160350.20810.0f
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发表时间：
2005-04-05
期刊：
影响因子：
37.8
通讯作者：
Kitakaze, M
中科院分区：
文献类型：
--
作者：
Li, Y;Minamino, T;Kitakaze, M
背景-平滑肌细胞的迁移、增殖和基质降解蛋白酶表达是血管损伤后内膜增生的主要特征。虽然MEK激酶1（MEKK 1）已被证明可以调节细胞迁移和尿激酶纤溶酶原激活剂（uPA）的表达，MEKK 1在这个过程中的确切作用仍然未知。方法和结果-我们触发了一个血管重塑模型完全结扎的右颈总动脉野生型（WT）和MEKK 1-null（MEKK 1（-/-））小鼠。结扎后28天，MEKK 1（-/-）动脉的内膜面积与WT动脉相比显著减少（28 +/- 8 vs 65 +/- 17 μ m（2），P < 0.05）。WT和MEKK 1（-/-）动脉之间的动脉壁内增殖细胞核抗原（PCNA）阳性细胞与总细胞的比率没有差异。WT和MEKK 1（-/-）培养的主动脉平滑肌细胞（AoSMC）之间的增殖能力也没有差异。相比之下，在MEKK 1（-/-）动脉中，结扎后7天内膜PCNA阳性细胞的数量显著较少。三种不同的迁移实验显示MEKK 1（-/-）AoSMCs的迁移和侵袭能力明显受损。添加全长MEKK 1恢复了MEKK 1（-/-）AoSMC的迁移能力。MEKK 1（-/-）AoSMCs显示由上皮生长因子形成的板状伪足的数量显著小于WT SMCs。结论MEKK 1通过调节平滑肌细胞的迁移和uPA的表达，参与血流阻断后的血管重构。MEKK 1是药物开发的潜在靶点，以防止血管重塑。
Background - Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown.Methods and Results - We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null ( MEKK1(-/-)) mice. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1(-/-) arteries compared with WT arteries ( 28 +/- 8 versus 65 +/- 17 mu m(2), P < 0.05). There were no differences in the ratios of proliferating cell nuclear antigen ( PCNA) - positive cells to total cells within the arterial wall between WT and MEKK1(-/-) arteries. Proliferation capacity also did not differ between WT and MEKK1(-/-) cultured aortic smooth muscle cells (AoSMCs). In contrast, the number of intimal PCNA-positive cells 7 days after ligation was significantly smaller in MEKK1(-/-) arteries. Three different migration assays revealed that migration and invasion of MEKK1(-/-) AoSMCs were markedly impaired. Addition of full-length MEKK1 restored the migration capacity of MEKK1(-/-) AoSMCs. The number of MEKK1(-/-) AoSMCs showing lamellipodia formation by epithelial growth factor was significantly smaller compared with those of WT SMCs. Furthermore, uPA expression after ligation was markedly decreased in MEKK1(-/-) arteries.Conclusions - MEKK1 is implicated in vascular remodeling after blood-flow cessation by regulating the migration and uPA expression of SMCs. MEKK1 is a potential target for drug development to prevent vascular remodeling.