Wnt5a/PKCδ信号通路介导氧化低密度脂蛋白诱导的巨噬细胞自噬

Autophagy of Macrophages Induced by Oxidized Low-Density Lipoprotein via Wnt5a/PKCδ Signaling Pathway

研究发现动脉粥样硬化(atherosclerosis,AS)斑块中巨噬细胞摄取氧化低密度脂蛋白(oxidized low-density lipoprotein, ox-LDL)和巨噬细胞极化等关键变化与失调性自噬关系密切. Wnt5a (wingless-type MMTV integration site family member 5a)在AS病变的富含巨噬细胞区域中高表达,然而Wnt5a是否参与巨噬细胞自噬尚未明确.本研究发现,60 mg/L ox-LDL处理Raw264.7细胞6 h时,自噬标志物LC3Ⅱ/Ⅰ显著增加,p62显著减少,且Wnt5a、PKCδ及STAT3的表达均增加.小分子干扰RNA (small interference RNA,si RNA)敲低Wnt5a后,逆转ox-LDL诱导的LC3Ⅱ/Ⅰ和PKCδ表达,上调p62表达,减少细胞内脂质蓄积. PKCδ抑制剂Rottlerin干预后,LC3Ⅱ/Ⅰ和STAT3减少,p62增加,降低细胞内脂质含量.综上,ox-LDL可能通过Wnt5a/PKCδ信号通路诱导巨噬细胞自噬.因此,深入研究Wnt5a/PKCδ通路在巨噬细胞及AS发生发展中的作用,是研究自噬机制新的着力点,并为药物干预提供新的靶点.

Evidence indicated that key changes in macrophage uptake of oxidized low density lipoprotein(oxLDL)and macrophage polarization in atherosclerotic plaques are closely related to dysfunctional autophagy.Wnt5 a(wingless-type MMTV integration site family member 5 a)is highly expressed in the macrophage-rich region of atherosclerosis(AS)lesions.However,whether Wnt5 a is involved in macrophages autophagy is not clear.In this study,we established macrophages-derived foam cell induced by ox-LDL to explore the effects of Wnt5 a/PKCδpathway on autophagy.RAW 264.7 macrophages were incubated with 60 mg/L ox-LDL for 6 h.The expression of autophagy marker,LC3Ⅱ/Ⅰwas significantly increased and p62 was decreased obviously.Moreover,the expressions of Wnt5 a,PCKδand STAT3 were also elevated.Knockdown of Wnt5 a reduced the expressions of LC3Ⅱ/Ⅰand PKCδ,induced the expression of p62,inhibited cellular lipid accumulation.Furthermore,PKCδinhibitor(Rottlerin)was downregulated the levels of LC3Ⅱ/Ⅰand STAT3,upregulated p62 level,inhibited cellular lipid accumulation.Therefore,ox-LDL induces autophagy in macrophages may be associated with Wnt5 a/PKCδsignaling pathway.The present study indicates that Wnt5 a/PKCδsignaling pathway may be underlying target for autophagy and drug intervention.