目的:探讨Th17/Treg平衡是否参与血红素氧合酶-1(heme oxygenase,HO-1)对ApoE-/-小鼠动脉粥样硬化斑块保护作用。方法:8周龄雄性ApoE-/-小鼠随机分为3组,给予8周西方饮食的同时,分别经腹腔注射0.9%氯化钠(对照组)、氯化血红素(诱导HO-1,HO-1组)和锌原卟啉(抑制HO-1,Zn组),并维持8周。8周后处死小鼠,检测斑块面积、斑块组分构成和HO-1表达、脾脏Th17与Treg比例、血浆IL-17、IL-6、IL-10和TGF-β1水平。结果:与对照组相比,HO-1组动脉内HO-1表达以及HO-1活性明显增加,伴随血浆脂质氢过氧化物(plasma lipid hydroperoxide,LPO)浓度降低。同时,HO-1组主动脉根处斑块显著减轻,且斑块更稳定,表现为平滑肌细胞、胶原增多,巨噬细胞和CD4^+细胞减少。进一步研究发现,HO-1组小鼠脾脏Th17比例显著降低,调节性T细胞(CD4^+CD25^+Foxp3^+)明显增高,血浆IL-17、IL-6水平降低,IL-10、TGF-β1水平升高。Zn组检测结果显示斑块明显加重,更趋于易损状态,且效应性/调节性T细胞(主要为Th17/Treg)失衡加剧。结论:HO-1通过调整Th17/Treg失衡抑制动脉粥样硬化进程。
Objective:The aim of this study was to investigate whether HO-1 ameliorates atherosclerosis by modulating the imbalance between Th17 and regulatory T cells(Treg)in ApoE-/-mice.Method:Intraperitoneal injections of saline as control(Control group),hemin to induce HO-1(HO-1 group),and Zn-protoporphyrin(ZnPP)Ⅸto inhibit HO-1(Zn group)were performed on 8 week old male ApoE-/-mice fed with western diet for 8 weeks.Atherosclerotic lesion size and component,the expression of HO-1,the frequencies of Th17(CD4^+IL-17+T cell)and Treg(CD4^+CD25^+Foxp3^+ +T cell)in spleen,and plasma levels of IL-17,IL-6,IL-10 and TGF-β1 were measured.Result:Compared with Control group,the arterial expression and activity of HO-1,and the plasma lipid hydroperoxide(LPO)levels were significantly increased in HO-1group,which showed obviously less mean atherosclerotic lesions in the aortic root,characteristic with increased smooth muscle cells,higher collagen concentration,however,decreased CD4+T cells and macrophages featuring a stable plague.Furthermore,the number of Treg was markedly increased in spleen in HO-1 group,whereas Th17 cells were reduced,accompanied with related cytokines expression altered accordingly in plasma.In contrast,inhibition of HO-1 by ZnPP induced augmented plaque progression and vulnerability along with imbalance of Th17/Treg.Conclusion:HO-1 attenuates atherosclerosis via regulating the imbalance of Th17/Treg in ApoE-/-mice.