Zhao Yihan, Zhao Yizhen, Tian Yuan, Zhou Yang
Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China.
The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
Exp Ther Med. 2022 Aug 24;24(4):636. doi: 10.3892/etm.2022.11573. eCollection 2022 Oct.
Numerous studies have shown that the formation of foam cells is of vital importance in the process of atherosclerosis. The aim of the present study was to assess the effects of metformin on foam cell formation in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells and explore its associated mechanism of action. Human monocytic THP-1 cells were pretreated with metformin for 2 h and subsequently treated with ox-LDL for 24 h. The data indicated that metformin significantly inhibited lipid accumulation in ox-LDL-treated THP-1 cells by decreasing the expression of scavenger receptor A, cluster of differentiation 36 and adipocyte enhancer-binding protein 1. In addition, metformin increased the expression levels of scavenger receptor B1 and ATP binding cassette transporter G1 and suppresses the esterification of free cholesterol. Furthermore, it markedly inhibited ferroptosis (reflected by the upregulation of glutathione peroxidase glutathione peroxidase 4 and the downregulation of Heme oxygenase-1). In addition, it caused a marked suppression in the expression levels of cysteinyl aspartate specific proteinase-1, IL-1β, NOD-like receptor protein 3, IL-18 secretion and in the levels of oxidative stress. Metformin attenuated the activation of ERK and facilitated the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK). Treatment of THP-1 cells with an ERK inhibitor reversed these effects, while inhibition of AMPK activity exacerbated the effects noted in ox-LDL-treated THP-1 cells. In conclusion, the present study suggested that metformin suppressed foam cell formation, inflammatory responses and inhibited ferroptosis in ox-LDL-treated macrophages via the AMPK/ERK signaling pathway.
大量研究表明，泡沫细胞的形成在动脉粥样硬化过程中至关重要。本研究旨在评估二甲双胍对氧化低密度脂蛋白（ox-LDL）处理的THP-1细胞中泡沫细胞形成的影响，并探讨其相关作用机制。人单核THP-1细胞先用二甲双胍预处理2小时，随后用ox-LDL处理24小时。数据表明，二甲双胍通过降低清道夫受体A、分化簇36和脂肪细胞增强子结合蛋白1的表达，显著抑制ox-LDL处理的THP-1细胞中的脂质积累。此外，二甲双胍增加了清道夫受体B1和ATP结合盒转运体G1的表达水平，并抑制游离胆固醇的酯化。此外，它显著抑制铁死亡（表现为谷胱甘肽过氧化物酶4上调和血红素加氧酶-1下调）。此外，它还导致半胱天冬酶-1、IL-1β、NOD样受体蛋白3、IL-18分泌的表达水平以及氧化应激水平显著降低。二甲双胍减弱了ERK的激活，并促进了5'腺苷单磷酸激活蛋白激酶（AMPK）的磷酸化。用ERK抑制剂处理THP-1细胞可逆转这些作用，而抑制AMPK活性则加剧了ox-LDL处理的THP-1细胞中的上述作用。总之，本研究表明，二甲双胍通过AMPK/ERK信号通路抑制ox-LDL处理的巨噬细胞中泡沫细胞的形成、炎症反应并抑制铁死亡。
