MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription.
MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription.
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MKL1 通过调节 FOXM1 转录促进 ROS 诱导的血管平滑肌细胞增殖
DOI：
10.1016/j.redox.2022.102586
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发表时间：
2023-02
期刊：
影响因子：
11.4
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Wu, Teng;Li, Nan;Zhang, Qiumei;Liu, Ruiqi;Zhao, Hongwei;Fan, Zhiwen;Zhuo, Lili;Yang, Yuyu;Xu, Yong
关键词：
活性氧（ROS）部分通过刺激血管平滑肌细胞（VSMC）增殖促进血管损伤和新生内膜形成。然而，潜在的转录机制尚未完全理解。在这里，我们报告了在经典的血管损伤模型中，小鼠中VSMC特异性MKL 1缺失抑制了新生内膜的形成。同样，CCG-1423对MKL 1活性的药物抑制也类似地缓和了小鼠中的新生内膜形成。在血管平滑肌细胞中组成型活性MKL 1的过度表达以ROS依赖的方式增强增殖。相反，MKL 1耗竭或抑制减弱VSMC增殖。基于PCR阵列的筛选将叉头盒蛋白M1（FOXM 1）鉴定为MKL 1的直接靶标。MKL 1与E2 F1相互作用，激活FOXM 1表达。一致地，FOXM 1耗竭改善MKL 1依赖性VSMC增殖。感兴趣的是，ROS诱导的MKL 1通过MK2磷酸化对于其与E2 F1的相互作用以及随后的FOXM 1反式激活是必需的。重要的是，在再狭窄患者的动脉标本中发现FOXM 1表达与VSMC增殖呈正相关。综上所述，我们的数据表明，MKL 1的氧化还原敏感性磷酸化开关激活FOXM 1转录并介导ROS刺激的血管平滑肌增殖。靶向MK-2/MKL 1/FOXM 1轴可能被认为是治疗再狭窄的合理方法。
Reactive oxygen species (ROS) promotes vascular injury and neointima formation in part by stimulating proliferation of vascular smooth muscle cells (VSMC). The underlying transcriptional mechanism, however, is not completely understood. Here we report that VSMC-specific deletion of MKL1 in mice suppressed neointima formation in a classic model of vascular injury. Likewise, pharmaceutical inhibition of MKL1 activity by CCG-1423 similarly mollified neointima formation in mice. Over-expression of a constitutively active MKL1 in vascular smooth muscle cells enhanced proliferation in a ROS-dependent manner. On the contrary, MKL1 depletion or inhibition attenuated VSMC proliferation. PCR array based screening identified forkhead box protein M1 (FOXM1) as a direct target for MKL1. MKL1 interacted with E2F1 to activate FOXM1 expression. Concordantly, FOXM1 depletion ameliorated MKL1-dependent VSMC proliferation. Of interest, ROS-induced MKL1 phosphorylation through MK2 was essential for its interaction with E2F1 and consequently FOXM1 trans-activation. Importantly, a positive correlation between FOXM1 expression and VSMC proliferation was identified in arterial specimens from patients with restenosis. Taken together, our data suggest that a redox-sensitive phosphorylation-switch of MKL1 activates FOXM1 transcription and mediates ROS fueled vascular smooth muscle proliferation. Targeting the MK-2/MKL1/FOXM1 axis may be considered as a reasonable approach for treatment of restenosis.
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