Li Lanfang, Mou Junyu, Han Yanwei, Wang Min, Lu Shan, Ma Qiuxiao, Wang Jialu, Ye Jingxue, Sun Guibo
Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; School of Pharmacy, Harbin University of Commerce, Harbin, China.
Int Immunopharmacol. 2023 Apr;117:109730. doi: 10.1016/j.intimp.2023.109730. Epub 2023 Mar 4.
Glycolysis-mediated macrophage polarization plays a crucial role in atherosclerosis. Although it is known that calenduloside E (CE) exerts anti-inflammatory and lipid-lowering effects in atherosclerosis, the underlying mechanism of action is not clearly understood. We hypothesized that CE functions by inhibiting M1 macrophage polarization via regulation of glycolysis. To verify this hypothesis, we determined the effects of CE in apolipoprotein E deficient (ApoE) mice and on macrophage polarization in oxidized low-density lipoprotein (ox-LDL)-induced RAW 264.7 macrophages and peritoneal macrophages. We also determined whether these effects are linked to regulation of glycolysis both in vivo and in vitro. The plaque size was reduced, and serum cytokine levels were decreased in the ApoE +CE group compared with that in the model group. CE decreased lipid droplet formation, inflammatory factor levels, and mRNA levels of M1 macrophage markers in ox-ldl-induced macrophages. CE suppressed ox-ldl-induced glycolysis, lactate levels, and glucose uptake. The relationship between glycolysis and M1 macrophage polarization was demonstrated using the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one. CE substantially upregulated ox-ldl-induced Kruppel-like transcription factor (KLF2) expression, and the effects of CE on ox-ldl-induced glycolysis and inflammatory factor levels disappeared after KLF2 knockdown. Together, our findings suggest that CE alleviates atherosclerosis by inhibiting glycolysis-mediated M1 macrophage polarization through upregulation of KLF2 expression, providing a new strategy for the treatment of atherosclerosis.
糖酵解介导的巨噬细胞极化在动脉粥样硬化中起关键作用。尽管已知金盏花苷E（CE）在动脉粥样硬化中发挥抗炎和降脂作用，但其潜在作用机制尚不清楚。我们推测CE通过调节糖酵解来抑制M1巨噬细胞极化发挥作用。为验证这一假设，我们确定了CE对载脂蛋白E缺陷（ApoE）小鼠以及对氧化型低密度脂蛋白（ox-LDL）诱导的RAW 264.7巨噬细胞和腹腔巨噬细胞中巨噬细胞极化的影响。我们还确定了这些作用在体内和体外是否与糖酵解的调节有关。与模型组相比，ApoE + CE组的斑块大小减小，血清细胞因子水平降低。CE减少了ox-LDL诱导的巨噬细胞中脂滴形成、炎症因子水平和M1巨噬细胞标志物的mRNA水平。CE抑制了ox-LDL诱导的糖酵解、乳酸水平和葡萄糖摄取。使用糖酵解抑制剂3-(3-吡啶基)-1-(4-吡啶基)-2-丙烯-1-酮证明了糖酵解与M1巨噬细胞极化之间的关系。CE显著上调了ox-LDL诱导的Kruppel样转录因子（KLF2）表达，KLF2敲低后，CE对ox-LDL诱导的糖酵解和炎症因子水平的影响消失。总之，我们的研究结果表明，CE通过上调KLF2表达抑制糖酵解介导的M1巨噬细胞极化来减轻动脉粥样硬化，为动脉粥样硬化的治疗提供了新策略。
