Smooth muscle-selective inhibition of nuclear factor-κB attenuates smooth muscle phenotypic switching and neointima formation following vascular injury.
Smooth muscle-selective inhibition of nuclear factor-κB attenuates smooth muscle phenotypic switching and neointima formation following vascular injury.
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DOI：
10.1161/jaha.113.000230
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发表时间：
2013-05-23
影响因子：
5.4
通讯作者：
Hayashi M
中科院分区：
文献类型：
--
作者：
Yoshida T;Yamashita M;Horimai C;Hayashi M
血管增殖性疾病如动脉粥样硬化是涉及多种细胞类型的炎症性疾病，包括巨噬细胞、淋巴细胞、内皮细胞和平滑肌细胞(SMC)。尽管血管中核因子-κB (NF-κB) 通路的激活已被证明对于血管疾病的进展至关重要，但 NF-κB 在 SMC 内的细胞自主作用尚未完全了解。我们生成了 SMC 选择性截短 IκB 表达 (SM22α-Cre/IκBΔN) 小鼠，其中 SMC 中 NF-κB 被选择性抑制，并分析了它们在颈动脉损伤后的表型。结果显示，SM22α-Cre/IκBΔN 小鼠受伤后新内膜形成明显减少。尽管血管损伤导致 SMC 分化标志物和心肌素（SMC 分化标志物的有效激活剂）表达下调，但这些标志物和心肌素的抑制在 SM22α-Cre/IκBΔN 小鼠中减弱。与这些发现一致的是，白细胞介素-1β (IL-1β) 激活的 NF-κB 降低了培养的 SMC 中 SMC 分化标志物以及心肌素的表达。 BAY 11-7082 对 NF-κB 信号传导的抑制减弱了 IL-1β 的抑制作用。有趣的是，Krüppel 样因子 4 (Klf4) 是一种对调节 SMC 分化和增殖至关重要的转录因子，也参与 IL-1β 介导的心肌素抑制。启动子分析和染色质免疫沉淀测定表明，NF-κB 通过与 Klf4 协同结合心肌素启动子区域来抑制心肌素。这些结果提供了新的证据，表明 NF-κB 通路的激活细胞自主介导 SMC 表型转换，并有助于血管损伤后新内膜的形成。
Vascular proliferative diseases such as atherosclerosis are inflammatory disorders involving multiple cell types including macrophages, lymphocytes, endothelial cells, and smooth muscle cells (SMCs). Although activation of the nuclear factor‐κB (NF‐κB) pathway in vessels has been shown to be critical for the progression of vascular diseases, the cell‐autonomous role of NF‐κB within SMCs has not been fully understood. We generated SMC‐selective truncated IκB expressing (SM22α‐Cre/IκBΔN) mice, in which NF‐κB was inhibited selectively in SMCs, and analyzed their phenotype following carotid injury. Results showed that neointima formation was markedly reduced in SM22α‐Cre/IκBΔN mice after injury. Although vascular injury induced downregulation of expression of SMC differentiation markers and myocardin, a potent activator of SMC differentiation markers, repression of these markers and myocardin was attenuated in SM22α‐Cre/IκBΔN mice. Consistent with these findings, NF‐κB activation by interleukin‐1β (IL‐1β) decreased expression of SMC differentiation markers as well as myocardin in cultured SMCs. Inhibition of NF‐κB signaling by BAY 11‐7082 attenuated repressive effects of IL‐1β. Of interest, Krüppel‐like factor 4 (Klf4), a transcription factor critical for regulating SMC differentiation and proliferation, was also involved in IL‐1β‐mediated myocardin repression. Promoter analyses and chromatin immunoprecipitation assays revealed that NF‐κB repressed myocardin by binding to the myocardin promoter region in concert with Klf4. These results provide novel evidence that activation of the NF‐κB pathway cell‐autonomously mediates SMC phenotypic switching and contributes to neointima formation following vascular injury.