轴突导向因子受体3缺陷促进化疗药物诱导的巨噬细胞泡沫化进程  

ROBO3 deficiency promotes chemotherapy⁃induced transition of macrophage to foam cell

作　　者：刘永 程晓雷 崔香丽[1] 唐颢 陈还珍[4] LIU Yong;CHENG XiaoLei;CUI Xiangli;TANG Hao;CHEN Huanzhen(Department of Physiology,School of Basic Medi-cine Sciences,Shanxi Medical University,Taiyuan 030012,China;不详)

机构地区：[1]山西医科大学基础医学院生理学系,太原030012 [2]南京鼓楼医院,南京210008 [3]国家心血管病中心华中分中心,郑州450003 [4]山西医科大学第一医院,太原030001

出　　处：《实用医学杂志》2024年第6期787-795,共9页The Journal of Practical Medicine

基　　金：河南省中青年卫生健康科技创新优秀青年人才培养项目(编号:YXKC2021050)。

摘　　要：目的 探索化疗药物阿霉素或顺铂对巨噬细胞脂质代谢的影响及调控机制。方法 阿霉素或者顺铂处理巨噬细胞RAW264.7,用油红O、ELISA等检测细胞内脂质水平;用RNA sequence和Western blot筛选和验证化疗药物处理后的基因表达变化;探讨沉默ROBO3对细胞脂质代谢的影响,并用Q-PCR和Western blot检测脂质代谢关键靶基因的变化。结果 阿霉素或顺铂可诱发巨噬细胞胆固醇代谢紊乱,加剧巨噬细胞泡沫化。进一步研究显示,轴突导向因子受体ROBO3的表达水平在化疗药物诱导巨噬细胞泡沫化进程中先增高后降低;沉默ROBO3加重oxldl诱导的巨噬细胞泡沫化水平。机制上,ROBO3沉默可上升胆固醇合成相关基因DHCR24表达,抑制胆固醇外排相关基因ABCG1表达,造成巨噬细胞内胆固醇蓄积。结论 ROBO3在化疗药物诱导巨噬细胞胆固醇代谢紊乱及泡沫化进程中发挥重要调控作用,可为化疗相关动脉粥样硬化的防治提供新的靶点和思路。Objective To explore the effect of chemotherapeutic drugs doxorubicin or cisplatin on lipid metabolism of macrophages and its regulatory mechanism.Methods Macrophage RAW264.7 was treated with doxorubicin or cisplatin,and intracellular lipid level was detected by oil red O and ELISA;RNA sequence screen-ing and Western blot were used to confirm the changes of gene expression after chemotherapeutic drug treatment;The effects of silencing ROBO3 on cellular lipid metabolism were explored,and changes in key target genes of lipid metabolism were detected by Q-PCR and western blot.Results Adriamycin or cisplatin induced disturbances in macrophage cholesterol metabolism and exacerbated macrophage foaminess.Further studies showed that the expression of the axon guidance factor receptor,ROBO3,increased and then decreased during the chemotherapeutic drug-induced macrophage foaming process.Further intervention with ROBO3 exacerbates oxldl-induced cholesterol accumulation and foam formation in macrophages.Mechanistically,ROBO3 deficiency promotes the expression of cholesterol synthesis-related gene DHCR24 and inhibits the expression of cholesterol elimination-related gene ABCG1,resulting in cholesterol accumulation in macrophages.Conclusion This study found that ROBO3 plays an important regulatory role in the disruption of cholesterol metabolism and its foaming process in macrophages induced by chemotherapeutic drugs,which may provide new targets and ideas for the prevention and treatment of chemotherapy-related atherosclerosis.

关 键 词：化疗血管毒性 巨噬-泡沫细胞 轴突导向因子受体3 胆固醇代谢 

分 类 号：R34[医药卫生—基础医学] Q789[生物学—分子生物学]