The scaffolding protein EBP50 promotes vascular smooth muscle cell proliferation and neointima formation by regulating Skp2 and p21(cip1).
The scaffolding protein EBP50 promotes vascular smooth muscle cell proliferation and neointima formation by regulating Skp2 and p21(cip1).
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DOI：
10.1161/atvbaha.111.235200
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Bisello A
中科院分区：
文献类型：
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作者：
Song GJ;Barrick S;Leslie KL;Bauer PM;Alonso V;Friedman PA;Fiaschi-Taesch NM;Bisello A
Ezrin-Radixin-Moesin结合磷蛋白50（EBP 50）是已知调节肾脏和肠中的离子稳态的支架蛋白。以前的研究表明，大鼠颈动脉球囊损伤后，EBP 50表达增加。本研究旨在探讨EBP 50在血管平滑肌细胞（VSMC）增殖和新生内膜增生中的作用。在野生型（WT）和EBP 50敲除（KO）小鼠中进行金属丝损伤。损伤后两周，KO小鼠的新生内膜形成比WT小鼠低80%。KO VSMC的增殖显著低于WT细胞，EBP 50的过表达增加VSMC的增殖。Akt活性和S期激酶蛋白2（Skp 2）的表达在KO细胞中降低，导致细胞周期蛋白依赖性激酶抑制剂p21 cip 1的稳定。因此，KO细胞被阻滞在G 0/G1期。与这些观察结果相一致，在KO而不是WT小鼠的受损股动脉中检测到p21 cip 1。未观察到WT和KO之间的细胞凋亡差异。EBP 50对新生内膜形成至关重要，并通过降低Skp 2稳定性诱导VSMC增殖，从而加速细胞周期抑制剂p21 cip 1的降解。
The Ezrin-Radixin-Moesin-Binding Phosphoprotein 50 (EBP50) is a scaffolding protein known to regulate ion homeostasis in the kidney and intestine. Previous work showed that EBP50 expression increases after balloon injury in rat carotids. This study was designed to determine the role of EBP50 on vascular smooth muscle cells (VSMC) proliferation and the development of neointimal hyperplasia. Wire injury was performed in wild type (WT) and EBP50 knockout (KO) mice. Two weeks after injury, neointima formation was 80% lower in KO than in WT mice. Proliferation of KO VSMC was significantly lower than WT cells and overexpression of EBP50 increased VSMC proliferation. Akt activity and expression of S-phase kinase protein 2 (Skp2) decreased in KO cells resulting in the stabilization of the cyclin-dependent kinase inhibitor, p21cip1. Consequently, KO cells were arrested in G0/G1 phase. Consistent with these observations, p21cip1 was detected in injured femoral arteries of KO but not WT mice. No differences in apoptosis between WT and KO were observed. EBP50 is critical for neointima formation and induces VSMC proliferation by decreasing Skp2 stability, thereby accelerating the degradation of the cell cycle inhibitor p21cip1.