p21Cip1 modulates arterial wound repair through the stromal cell-derived factor-1/CXCR4 axis in mice
p21Cip1 modulates arterial wound repair through the stromal cell-derived factor-1/CXCR4 axis in mice
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DOI：
10.1172/jci31244
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发表时间：
2008-06-01
影响因子：
15.9
通讯作者：
Boehm, Manfred
中科院分区：
文献类型：
--
作者：
Olive, Michelle;Mellad, Jason A.;Boehm, Manfred
细胞周期蛋白依赖性激酶抑制剂，包括p21（Cip 1），涉及细胞更新，是心血管伤口修复的积极参与者。在这里，我们表明，p21（Cip 1）协调血管创伤修复过程中局部血管和循环免疫细胞之间的复杂相互作用。为了应对股动脉机械损伤，p21纯合缺失（Cip 1）的小鼠表现出VSMC增殖加速和免疫细胞浸润增加。骨髓移植实验表明，局部p21（Cip 1）在抑制血管创伤修复过程中的过度增殖中起着关键作用。在p21（+/+）和p21（-/-）小鼠股动脉损伤后观察到局部血管基质细胞衍生因子-1（SDF-1）水平升高，尽管p21（-/-）动物中SDF-1水平显著更高。此外，在p21（+/+）和p21（-/-）小鼠中，SDF-1/CXCR 4信号传导的破坏抑制了血管重塑期间的增殖反应。我们提供的证据表明，JAK/STAT信号通路是血管SDF-1水平的重要调节因子，P21（Cip 1）抑制STAT 3结合到小鼠SDF-1启动子内的STAT结合位点。总的来说，这些结果表明，p21（Cip 1）活性是必不可少的调节细胞，增殖和炎症后动脉损伤局部血管细胞和SDF-1/CXCR 4信号系统是血管增殖的关键介质，在响应损伤。
Cyclin-dependent kinase inhibitors, including p21(Cip1), are implicated in cell turnover and are active players in cardiovascular wound repair. Here, we show that p21(Cip1) orchestrates the complex interactions between local vascular and circulating immune cells during vascular wound repair. In response to femoral artery mechanical injury, mice with homozygous deletion of p21(Cip1) displayed accelerated proliferation of VSMCs and increased immune cell infiltration. BM transplantation experiments indicated that local p21(Cip1) plays a pivotal role in restraining excessive proliferation during vascular wound repair. Increased local vascular stromal cell-derived factor-1 (SDF-1) levels were observed after femoral artery injury in p21(+/+) and p21(-/-) mice, although this was significantly greater in p21(-/-) animals. In addition, disruption of SDF-1/CXCR4 signaling inhibited the proliferative response during vascular remodeling in both p21(+/+) and p21(-/-) mice. We provide evidence that the JAK/STAT signaling pathway is an important regulator of vascular SDF-1 levels and that P21(Cip1) inhibits STAT3 binding to the STAT-binding site within the murine SDF-1 promoter. Collectively, these results suggest that p21(Cip1) activity is essential for the regulation of cell, proliferation and inflammation after arterial injury in local vascular cells and that the SDF-1/CXCR4 signaling system is a key mediator of vascular proliferation in response to injury.