Qing-Xin-Jie-Yu Granule inhibits ferroptosis and stabilizes atherosclerotic plaques by regulating the GPX4/xCT signaling pathway
Qing-Xin-Jie-Yu Granule inhibits ferroptosis and stabilizes atherosclerotic plaques by regulating the GPX4/xCT signaling pathway
复制标题
清心解郁颗粒通过调控GPX4/xCT信号通路抑制铁死亡并稳定动脉粥样硬化斑块
DOI：
10.1016/j.jep.2022.115852
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发表时间：
2023
影响因子：
5.4
通讯作者：
Hao Xu
中科院分区：
文献类型：
--
作者：
Jie Zhang;Xinyi Wang;Baoyi Guan;Xue Wang;Xiaojing An;Tong Wang;Xuanye Chen;Lin Zhao;Jundi Jia;Luxia Song;Dan Ma;Qiuyi Li;He Zhang;Jianqing Ju;Hao Xu
清心解郁颗粒(QXJYG)是治疗动脉粥样硬化性(AS)心血管疾病的综合中药方剂。一项随机对照试验发现清心降脂颗粒可减少心血管事件的发生，实验也证实其通过重塑肠道菌群来减轻AS。目的研究清心降脂颗粒是否通过调节高脂饮食诱导的动脉粥样硬化ApoE-/-小鼠的铁下垂来减轻AS和斑块的易感性，并观察其对RAS-选择性致死3(RSL3)诱导的J744A.1细胞巨噬细胞铁下垂的影响。免疫组织化学和免疫印迹法检测谷胱甘肽过氧化物酶4(Gpx4)/半胱氨酸谷氨酸反向转运体(XCT)信号通路。清肾降逆颗粒治疗组动物出现典型的铁性下垂的形态改变。清肾降肾冲剂组大鼠血清总铁含量明显低于模型组(P<；P<0.05)，其抑制脂质过氧化水平(丙二醛)，增强机体抗氧化能力(超氧化物歧化酶和谷胱甘肽)，降低与铁性下垂相关的炎症因子(IL-6、IL-1β、肿瘤坏死因子-α)。清心降银颗粒组大鼠主动脉组织中Gpx4/XCT的表达明显增加。清肾降逆颗粒抑制RSL3干扰的J744A.1巨噬细胞铁下垂。清肺降逆颗粒组的Fe2+、LPO和活性氧水平均低于RSL3组(P<；P<0.05)。结论清肾降逆颗粒部分通过Gpx4/XCT信号通路抑制AS易损性斑块的铁下垂。
Ethnopharmacological relevanceQing-Xin-Jie-Yu Granule (QXJYG) is an integrated traditional Chinese medicine formula used to treat atherosclerotic (AS) cardiovascular diseases. A randomized controlled trial found that QXJYG reduced cardiovascular events and experiments also verified that QXJYG attenuated AS by remodeling the intestinal flora.Aim of the studyTo determine whether QXJYG would attenuate AS and plaque vulnerability by regulating ferroptosis in high-fat diet-induced atherosclerotic ApoE-/-mice and to investigate the effects of QXJYG on macrophage ferroptosis in RAS-selective lethal 3 (RSL3)-induced J744A.1 cells.MethodsAS models in ApoE-/-mice and RSL3-induced ferroptosis in J744A.1 cells were established to measure the protective and anti-ferroptotic effects of QXJYGin vivoandin vitro. The glutathione peroxidase 4 (GPX4)/cystine glutamate reverse transporter (xCT) signal pathway was examined by immunohistochemistry and western blotting.ResultsQXJYG attenuated AS progression and plaque vulnerability. Characteristic morphological changes of ferroptosis in the QXJYG-treated animals were rare. Total iron was significantly lower in the QXJYG group than in the model group (P< 0.05); QXJYG suppressed the lipid peroxidation (LPO) levels (malondialdehyde), enhanced the antioxidant capacity (superoxide dismutase and glutathione), and reduced inflammatory factors (interleukin [IL]-6, IL-1β, tumor necrosis factor-α) associated with ferroptosis. Expression of GPX4/xCT in aorta tissues was remarkably increased in the QXJYG group. QXJYG inhibited ferroptosis in J744A.1 macrophages disturbed using RSL3. The Fe2+, LPO, and reactive oxygen species levels were lower in the QXJYG group than in the RSL3 group (P< 0.05). The QXJYG group showed higher expression of the GPX4/xCT signal pathway.ConclusionQXJYG inhibits ferroptosis in vulnerable AS plaques partially via the GPX4/xCT signaling pathway.