Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia
Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia
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DOI：
10.1074/jbc.m502149200
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发表时间：
2005-08-19
影响因子：
4.8
通讯作者：
Aird, WC
中科院分区：
文献类型：
--
作者：
Abid, MR;Yano, K;Aird, WC
血管平滑肌细胞（VSMC）的增殖和迁移在动脉粥样硬化、血管成形术后再狭窄和移植血管病变中起重要作用。叉头转录因子属于FoxO亚家族，已被证明在多种细胞类型中抑制生长和细胞周期进程。我们假设叉头蛋白可能在VSMC生物学中发挥作用。在体外条件下，血小板衍生生长因子(PDGF)- bb、肿瘤坏死因子- α和胰岛素样生长因子1通过MEK1/2和/或磷脂酰肌醇3激酶依赖的信号通路刺激人冠状动脉平滑肌细胞FoxO的磷酸化。PDGF-BB、肿瘤坏死因子α和胰岛素样生长因子1治疗导致FoxO的核排斥，而PDGF-BB单独下调FoxO靶基因p27(kip1)，并通过细胞周期增强细胞存活和进展。FoxO家族成员TM-FKHRL1的组成型活性抗磷酸化突变体的过表达消除了这些影响。TM-FKHRL1的抗增殖作用被p27（kip1）的小干扰RNA部分逆转。在大鼠颈动脉球囊损伤模型中，腺病毒介导的FKHRL1基因转移引起VSMC中p27（kip1）表达增加，抑制新生内膜增生。这些数据表明FoxO活性抑制VSMC的增殖和激活，并且该信号轴可能代表血管病变状态的治疗靶点。
Vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to atherosclerosis, postangioplasty restenosis, and transplant vasculopathy. Forkhead transcription factors belonging to the FoxO subfamily have been shown to inhibit growth and cell cycle progression in a variety of cell types. We hypothesized that forkhead proteins may play a role in VSMC biology. Under in vitro conditions, platelet- derived growth factor (PDGF)-BB, tumor necrosis factor-alpha, and insulin-like growth factor 1 stimulated phosphorylation of FoxO in human coronary artery smooth muscle cells via MEK1/2 and/or phosphatidylinositol 3-kinase-dependent signaling pathways. PDGF-BB, tumor necrosis factor-alpha, and insulin-like growth factor 1 treatment resulted in the nuclear exclusion of FoxO, whereas PDGF-BB alone down-regulated the FoxO target gene, p27(kip1), and enhanced cell survival and progression through the cell cycle. These effects were abrogated by overexpression of a constitutively active, phosphorylationresistant mutant of the FoxO family member, TM-FKHRL1. The anti-proliferative effect of TM-FKHRL1 was partially reversed by small interfering RNA against p27(kip1). In a rat balloon carotid arterial injury model, adenovirus-mediated gene transfer of FKHRL1 caused an increase in the expression of p27(kip1) in the VSMC and inhibition of neointimal hyperplasia. These data suggest that FoxO activity inhibits VSMC proliferation and activation and that this signaling axis may represent a therapeutic target in vasculopathic disease states.