KIS protects against adverse vascular remodeling by opposing stathmin-mediated VSMC migration in mice
KIS protects against adverse vascular remodeling by opposing stathmin-mediated VSMC migration in mice
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DOI：
10.1172/jci33206
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发表时间：
2008-12-01
影响因子：
15.9
通讯作者：
Nabel, Elizabeth G.
中科院分区：
文献类型：
--
作者：
Langenickel, Thomas H.;Olive, Michelle;Nabel, Elizabeth G.
血管增生性疾病的特征在于VSMC增殖和迁移。与stathmin相互作用的激酶（KIS）靶向细胞增殖和迁移的2个关键调节因子，细胞周期蛋白依赖性激酶抑制剂P27（Kip 1）和微管不稳定蛋白stathmin。KIS对p27（Kip 1）的磷酸化导致细胞周期进展，而KIS介导的Stathmin磷酸化在VSMC中的靶序列和生理相关性尚不清楚。在这里，我们证明了KIS-/-小鼠的血管伤口修复导致了主要由VSMC组成的新生内膜的加速形成。KIS的缺失增加了VSMC的迁移活性和胞质微管蛋白的不稳定活性，但通过延迟核输出和p27（Kip 1）的降解而废除了VSMC的增殖。这种促迁移表型是由stathmin蛋白水平增加引起的，这是由于缺乏KIS介导的stathmin丝氨酸38磷酸化和stathmin蛋白降解减少引起的。KTS-/- VSMCs中stathmin的下调完全恢复了表型，并且stathmin缺陷小鼠表现出对血管损伤的反应减少了病变形成。这些数据表明，KIS通过对抗stathmin介导的VSMC迁移来防止过度新生内膜形成，并且VSMC迁移代表了血管伤口修复的主要机制，构成了治疗干预的相关靶点和机制。
Vascular proliferative diseases are characterized by VSMC proliferation and migration. Kinase interacting with stathmin (KIS) targets 2 key regulators of cell proliferation and migration, the cyclin-dependent kinase inhibitor P27(Kip1) and the microtubule-destabilizing protein stathmin. Phosphorylation of p27(Kip1) by KIS leads to cell-cycle progression, whereas the target sequence and the physiological relevance of KIS-mediated stathmin phosphorylation in VSMCs are unknown. Here we demonstrated that vascular wound repair in KIS-/- mice resulted in accelerated formation of neointima, which is composed predominantly of VSMCs. Deletion of KIS increased VSMC migratory activity and cytoplasmic tubulin destabilizing activity, but abolished VSMC proliferation through the delayed nuclear export and degradation of p27(Kip1). This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of KIS-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation. Downregulation of stathmin in KTS-/- VSMCs fuilly restored the phenotype, and stathmin-deficient mice demonstrated reduced lesion formation in response to vascular injury. These data suggest that KIS protects against excessive neointima formation by opposing stathmin-mediated VSMC migration and that VSMC migration represents a major mechanism of vascular wound repair, constituting a relevant target and mechanism for therapeutic interventions.