Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Department of Human Anatomy, Nanjing Medical University, Nanjing, China.
Redox Biol. 2023 Feb;59:102586. doi: 10.1016/j.redox.2022.102586. Epub 2022 Dec 29.
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.
活性氧（ROS）通过刺激血管平滑肌细胞（VSMC）增殖，在部分程度上促进血管损伤和新生内膜形成。然而，其潜在的转录机制尚未完全阐明。本研究报道，MKL1 在小鼠血管平滑肌细胞中的特异性缺失抑制了经典血管损伤模型中的新生内膜形成。同样，MKL1 活性的药物抑制（如 CCG-1423）也能减轻小鼠的新生内膜形成。血管平滑肌细胞中组成性激活的 MKL1 的过表达以 ROS 依赖的方式增强增殖。相反，MKL1 的缺失或抑制会减弱 VSMC 的增殖。基于 PCR 阵列的筛选鉴定出叉头框蛋白 M1（FOXM1）是 MKL1 的直接靶标。MKL1 与 E2F1 相互作用激活 FOXM1 的表达。相应地，FOXM1 的缺失减轻了 MKL1 依赖的 VSMC 增殖。有趣的是，ROS 通过 MK2 诱导的 MKL1 磷酸化对于其与 E2F1 的相互作用以及 FOXM1 的转录激活至关重要。重要的是，在再狭窄患者的动脉标本中发现了 FOXM1 表达与 VSMC 增殖之间的正相关性。总之，我们的数据表明，MKL1 的氧化还原敏感磷酸化开关激活了 FOXM1 转录并介导了 ROS 驱动的血管平滑肌增殖。靶向 MK-2/MKL1/FOXM1 轴可能被认为是治疗再狭窄的合理方法。
