Graduate School, Tianjin Medical University, Qixiangtai Road No. 22, Tianjin 300070, China; Institute of Cardiovascular Disease and Heart Center, Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Chinese People's Armed Police Force (PAP) Medical Center, Chenglin Road No. 220, Hedong District, Tianjin 300162, China.
Department of Thoracic Surgery, Medical Collage of People's Liberation Army (PLA), PLA General Hospital, Fuxing Road No. 28, Haidian District, Beijing 100853, China; Tianjin Key Laboratory of Neurotrauma Repair, Institute of Brain Trauma and Neurology Disease, Center for Neurology and Neurosurgery, Chinese People's Armed Police Force (PAP) Medical Center, Chenglin Road No. 220, Hedong District, Tianjin 300162, China.
Biomed Pharmacother. 2019 Dec;120:109352. doi: 10.1016/j.biopha.2019.109352. Epub 2019 Oct 3.
Inflammatory monocyte and macrophage subset accumulation during the inflammatory response that drives atherosclerosis can exacerbate the extent of atherosclerosis. It has been demonstrated that voltage-gated sodium channels (VGSCs) can regulate cell bioactivities in monocytes/macrophages. We hypothesized that blockade of mononuclear phagocyte VGSCs was atheroprotective through monocyte/macrophage subset modulation and macrophage proliferation suppression in atherosclerotic lesions. In this experimental study, when VGSCs were knocked down with RNA interference plasmid transfection in mouse peripheral blood monocytes and monocyte-macrophage lineage RAW264.7 cells in vitro, the biological characteristics of proliferation, phagocytosis, and migration in RAW264.7 cells declined. In addition, suppression of LPS-induced M1 polarization and facilitation of IL-4-induced M2 polarization were also observed. In an in vivo study, ApoE knockout (ApoE) mice were fed a standard chow diet (CD) or a western diet (WD). After feeding with phenytoin (PHT), no significant differences were detected in plasma lipids, and the anti-inflammatory phenotypes of both monocytes and macrophages were elevated and proinflammatory phenotypes declined. The local proliferation of macrophages was also distinctly suppressed, along with a significant reduction in atheromatous plaques. In conclusion, blockade of VGSCs in the mononuclear phagocyte system reduced atherosclerotic lesions, which may occur through altering monocyte/macrophage subsets and suppressing macrophage proliferation in atherosclerotic plaques. Blockage of VGSCs may play an important role in cardiovascular protection.
在驱动动脉粥样硬化的炎症反应中，炎症性单核细胞和巨噬细胞亚群的积累会加剧动脉粥样硬化的程度。已经证明，电压门控钠离子通道（VGSCs）可以调节单核细胞/巨噬细胞中的细胞生物活性。我们假设，通过调节单核细胞/巨噬细胞亚群和抑制动脉粥样硬化病变中的巨噬细胞增殖，阻断单核吞噬细胞 VGSCs 具有抗动脉粥样硬化作用。在这项实验研究中，当通过 RNA 干扰质粒转染在体外敲低小鼠外周血单核细胞和单核巨噬细胞系 RAW264.7 细胞中的 VGSCs 时，RAW264.7 细胞的增殖、吞噬和迁移等生物学特性下降。此外，还观察到抑制 LPS 诱导的 M1 极化和促进 IL-4 诱导的 M2 极化。在体内研究中，apoE 基因敲除（ApoE）小鼠给予标准饲料（CD）或西方饮食（WD）。用苯妥英（PHT）喂养后，血浆脂质无明显差异，单核细胞和巨噬细胞的抗炎表型升高，促炎表型下降。巨噬细胞的局部增殖也明显受到抑制，动脉粥样硬化斑块显著减少。总之，单核吞噬细胞系统中 VGSCs 的阻断减少了动脉粥样硬化病变，这可能是通过改变单核细胞/巨噬细胞亚群和抑制动脉粥样硬化斑块中的巨噬细胞增殖来实现的。阻断 VGSCs 可能在心血管保护中发挥重要作用。
