A Novel Anticancer Therapeutic Strategy to Target Autophagy Accelerates Radiation-Associated Atherosclerosis
A Novel Anticancer Therapeutic Strategy to Target Autophagy Accelerates Radiation-Associated Atherosclerosis
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一种针对自噬的新型抗癌治疗策略可加速放射相关的动脉粥样硬化
DOI：
10.1016/j.ijrobp.2020.09.007
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发表时间：
2021-01-07
影响因子：
7
通讯作者：
He, Ben
中科院分区：
文献类型：
--
作者：
Yuan, Ruosen;Sun, Zhe;He, Ben
目的：自噬抑制是一种治疗晚期癌症的新策略，特别是那些接受过放射治疗的患者。在本研究中，我们研究了自噬抑制剂是否会加速辐射相关性动脉粥样硬化（RAA）的进展。方法与材料：8周龄载脂蛋白（ApoE(-/-)）小鼠饲喂西式饮食，结扎左颈总动脉诱导动脉粥样硬化。4周后，用5或10 Gy剂量的局部电离辐射（IR）诱导左颈总动脉RAA。再过4周，观察到严重的斑块负担与巨噬细胞浸润和脂质沉积增加、平滑肌细胞减少和胶原表达减少有关。此外，这些变化以剂量依赖的方式发生。在体外实验中，在动脉粥样硬化斑块的巨噬细胞和腹腔巨噬细胞中均观察到IR引起的自噬通量的增加。氯喹（50 mg/kg/d）对自噬流量的抑制进一步加速了ApoE（-/-）小鼠左颈总动脉RAA的进展。此外，氯喹治疗加剧了ir诱导的腹腔巨噬细胞p65核易位、IKBot降解和核因子κ B （nf - κ B）靶基因的转录。结论：IR促进动脉粥样硬化形成，增加自噬通量。此外，氯喹的自噬抑制作用通过刺激巨噬细胞nf - κ b介导的炎症反应来加速RAA病变的进展。(C) 2020爱思唯尔公司版权所有。
Purpose: Autophagy inhibition is a novel therapeutic strategy suggested for patients with advanced cancer, especially those who have undergone radiation therapy. In the present study, we investigated whether autophagy inhibitors accelerate the progression of radiation-associated atherosclerosis (RAA).Methods and Materials: Eight-week-old apolipoprotein (ApoE(-/-)) mice were fed a Western diet, and their left common carotid arteries were partially ligated to induce atherogenesis. Four weeks later, local ionizing radiation (IR) at a dose of 5 or 10 Gy was used to induce RAA in the left common carotid artery. After another 4 weeks, severe plaque burden associated with increased macrophage infiltration and lipid deposition, reduced smooth muscle cells, and decreased collagen expression was observed. In addition, these changes occurred in a dose-dependent manner. Improved autophagic flux caused by IR was observed in both macrophages of the atherosclerotic plaque and peritoneal macrophages in vitro. The inhibition of autophagic flux by chloroquine (50 mg/kg/d) further accelerated the progression of RAA in the left common carotid arteries of ApoE(-/-) mice. Furthermore, chloroquine treatment exacerbated IR-induced p65 nuclear translocation, IKBot degradation, and transcription of nuclear factor-kappa B (NF-kappa B) target genes in peritoneal macrophages.Conclusions: IR promotes atherogenesis and increases autophagic flux. In addition, autophagy inhibition by chloroquine accelerates the progression of RAA lesions by stimulating NF-kappa B-mediated inflammatory responses in macrophages. (C) 2020 Elsevier Inc. All rights reserved.