New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway
New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway
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PCSK9 在涉及 TLR4/NF-κ B 通路的动脉粥样硬化炎症促进中的新作用
DOI：
10.1016/j.atherosclerosis.2017.04.023
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发表时间：
2017-07-01
期刊：
影响因子：
5.3
通讯作者：
Jiang, Zhi-Sheng
中科院分区：
文献类型：
--
作者：
Tang, Zhi-Han;Peng, Juan;Jiang, Zhi-Sheng
背景和目的：原蛋白转换酶枯草杆菌/可可素9(PCSK9)已成为开发新的降胆固醇药物和动脉粥样硬化治疗干预措施的热门靶点。PCSK9可通过肝脏低密度脂蛋白受体降解以外的机制加速动脉粥样硬化。多项临床研究表明，PCSK9与动脉粥样硬化性炎症有关。因此，本研究旨在探讨PCSK9在促进动脉粥样硬化进展的血管炎症中的作用。方法：我们通过慢病毒介导的PCSK9 shRNA(LV-PCSK9 shRNA)载体转导PCSK9沉默是否影响高脂血症诱导的动脉粥样硬化(ApoE KO)小鼠血管病变的形成。体外应用LV-PCSK9和LV-PCSK9 shRNA研究PCSK9过表达和PCSK9沉默对oxLDL诱导的巨噬细胞炎症的影响。结果：免疫组织化学分析显示，apoE KO小鼠动脉粥样硬化斑块内PCSK9表达增加。这些体内结果表明，与对照组相比，LV-PCSK9 shRNA组小鼠出现的动脉粥样硬化斑块较少。巨噬细胞数量减少，肿瘤坏死因子-α、白介素1-β、单核细胞趋化蛋白-1、Toll样受体4和核因子-kappaB等血管炎症调节因子表达减少。我们进一步表明，在体外巨噬细胞中过表达PCSK9会增加oxLDL诱导的促炎细胞因子的分泌。在oxLDL处理的巨噬细胞中，PCSK9过表达上调TLR4的表达，增加p-I kappaBα水平、IkBα降解和核转录因子kappaB的核转位，而PCSK9基因下调的作用则相反。结论：PCSK9基因干扰可直接抑制动脉粥样硬化，其机制可能与抑制高脂饮食喂养的apoE KO小鼠血管炎症和抑制TLR4/NF-kappa B信号通路有关，而不影响血浆胆固醇水平。PCSK9可能是动脉粥样硬化发病机制中的一种炎症介质。(C)2017爱思唯尔B.V.保留所有权利。
Background and aims: Proprotein convertase subtilisin/kexin 9 (PCSK9) has emerged as a popular target in the development of new cholesterol-lowering drugs and therapeutic interventions for atherosclerosis. PCSK9 could accelerate atherosclerosis through mechanisms beyond the degradation of the hepatic lowdensity lipoprotein receptor. Several clinical studies suggested that PCSK9 is involved in atherosclerotic inflammation. Accordingly, this study aimed to explore the role of PCSK9 in vascular inflammation that promotes atherosclerotic progression.Methods: We examined whether PCSK9 silencing via transduction with the lentivirus-mediated PCSK9 shRNA (LV-PCSK9 shRNA) vector affects the formation of vascular lesions in hyperlipidemia-induced atherosclerosis in apolipoprotein E knockout (apoE KO) mice. In vitro, the effects of PCSK9 on oxLDLinduced macrophages inflammation were investigate using LV-PCSK9 and LV-PCSK9 shRNA for PCSK9 overexpression and PCSK9 silencing.Results: Immunohistochemical analysis showed that PCSK9 expression increased within atherosclerotic plaques in apoE KO mice. These in vivo results showed that the LV-PCSK9 shRNA group of mice developed less aortic atherosclerotic plaques compared with the control group. These lesions also had the reduced number of macrophages and decreased expression of vascular inflammation regulators, such as tumor necrosis factor-alpha, interleukin 1 beta, monocyte chemoattractant protein-1, toll-like receptor 4 and nuclear factor kappa B (NF-kappa B). We further showed that PCSK9 overexpression in macrophages in vitro increased the secretion of oxLDL-induced proinflammatory cytokines. PCSK9 overexpression upregulated TLR4 expression and increased p-I kappa B alpha levels, IkB alpha degradation, and NF-kappa B nuclear translocation in macrophages, but PCSK9 knockdown had the opposite effects in oxLDL-treated macrophages.Conclusions: PCSK9 gene interference could suppress atherosclerosis directly through decreasing vascular inflammation and inhibiting the TLR4/NF-kappa B signaling pathway without affecting plasma cholesterol level in high-fat diet-fed apoE KO mice. PCSK9 may be an inflammatory mediator in the pathogenesis of atherosclerosis. (C) 2017 Elsevier B.V. All rights reserved.