Deletion of Krüppel-like factor 4 in endothelial and hematopoietic cells enhances neointimal formation following vascular injury.
Deletion of Krüppel-like factor 4 in endothelial and hematopoietic cells enhances neointimal formation following vascular injury.
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DOI：
10.1161/jaha.113.000622
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发表时间：
2014-01-27
影响因子：
5.4
通讯作者：
Hayashi M
中科院分区：
文献类型：
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作者：
Yoshida T;Yamashita M;Horimai C;Hayashi M
Krüppel 样因子 4 (Klf4) 通过激活或抑制多个基因的转录来参与多种细胞功能。先前的研究结果表明，小鼠中他莫昔芬诱导的 Klf4 基因整体缺失加速了血管损伤后的新内膜形成，部分是通过增强平滑肌细胞 (SMC) 的增殖来实现的。由于 Klf4 也在包括内皮细胞 (EC) 在内的非 SMC 中表达，因此我们确定 EC 和造血细胞中 Tie2 启动子依赖性 Klf4 缺失是否会影响损伤诱导的新内膜形成。通过交配Tie2-Cre小鼠和Klf4 floxed小鼠产生Klf4条件敲除（cKO）小鼠，并在颈动脉结扎损伤后分析其表型。结果表明，损伤诱导的 SMC 分化标志物抑制不受 Tie2 启动子依赖性 Klf4 缺失的影响。然而，有趣的是，颈动脉损伤后 21 天，Klf4-cKO 小鼠的新内膜形成显着增强。此外，Klf4-cKO小鼠的增殖率增加，巨噬细胞和T淋巴细胞的积累增加，受损动脉中细胞粘附分子的表达升高，包括血管细胞粘附分子-1（Vcam1）和E-选择素。培养 EC 的机制分析表明，Klf4 通过阻断核因子-κB 与 Vcam1 启动子的结合，抑制肿瘤坏死因子-α 诱导的 Vcam1 表达。这些结果提供了证据，证明 EC 等非 SMC 中的 Klf4 通过抑制血管损伤后的动脉炎症来调节新内膜形成。
Krüppel‐like factor 4 (Klf4) is involved in a variety of cellular functions by activating or repressing the transcription of multiple genes. Results of previous studies showed that tamoxifen‐inducible global deletion of the Klf4 gene in mice accelerated neointimal formation following vascular injury, in part via enhanced proliferation of smooth muscle cells (SMCs). Because Klf4 is also expressed in non‐SMCs including endothelial cells (ECs), we determined if Tie2 promoter‐dependent deletion of Klf4 in ECs and hematopoietic cells affected injury‐induced neointimal formation. Klf4 conditional knockout (cKO) mice were generated by breeding Tie2‐Cre mice and Klf4 floxed mice, and their phenotype was analyzed after carotid ligation injury. Results showed that injury‐induced repression of SMC differentiation markers was unaffected by Tie2 promoter‐dependent Klf4 deletion. However, of interest, neointimal formation was significantly enhanced in Klf4‐cKO mice 21 days following carotid injury. Moreover, Klf4‐cKO mice exhibited an augmented proliferation rate, enhanced accumulation of macrophages and T lymphocytes, and elevated expression of cell adhesion molecules including vascular cell adhesion molecule–1 (Vcam1) and E‐selectin in injured arteries. Mechanistic analyses in cultured ECs revealed that Klf4 inhibited tumor necrosis factor‐α–induced expression of Vcam1 through blocking the binding of nuclear factor‐κB to the Vcam1 promoter. These results provide evidence that Klf4 in non‐SMCs such as ECs regulates neointimal formation by repressing arterial inflammation following vascular injury.