Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Interventional Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
FASEB J. 2024 May 31;38(10):e23678. doi: 10.1096/fj.202400427RR.
Melatonin (MLT), a conserved small indole compound, exhibits anti-inflammatory and antioxidant properties, contributing to its cardioprotective effects. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with atherosclerosis disease risk, and is known as an atherosclerosis risk biomarker. This study aimed to investigate the impact of MLT on Lp-PLA2 expression in the atherosclerotic process and explore the underlying mechanisms involved. In vivo, ApoE mice were fed a high-fat diet, with or without MLT administration, after which the plaque area and collagen content were assessed. Macrophages were pretreated with MLT combined with ox-LDL, and the levels of ferroptosis-related proteins, NRF2 activation, mitochondrial function, and oxidative stress were measured. MLT administration significantly attenuated atherosclerotic plaque progression, as evidenced by decreased plaque area and increased collagen. Compared with those in the high-fat diet (HD) group, the levels of glutathione peroxidase 4 (GPX4) and SLC7A11 (xCT, a cystine/glutamate transporter) in atherosclerotic root macrophages were significantly increased in the MLT group. In vitro, MLT activated the nuclear factor-E2-related Factor 2 (NRF2)/SLC7A11/GPX4 signaling pathway, enhancing antioxidant capacity while reducing lipid peroxidation and suppressing Lp-PLA2 expression in macrophages. Moreover, MLT reversed ox-LDL-induced ferroptosis, through the use of ferrostatin-1 (a ferroptosis inhibitor) and/or erastin (a ferroptosis activator). Furthermore, the protective effects of MLT on Lp-PLA2 expression, antioxidant capacity, lipid peroxidation, and ferroptosis were decreased in ML385 (a specific NRF2 inhibitor)-treated macrophages and in AAV-sh-NRF2 treated ApoE mice. MLT suppresses Lp-PLA2 expression and atherosclerosis processes by inhibiting macrophage ferroptosis and partially activating the NRF2 pathway.
褪黑素（MLT）是一种保守的小分子吲哚化合物，具有抗炎和抗氧化特性，有助于其心脏保护作用。脂蛋白相关磷脂酶 A2（Lp-PLA2）与动脉粥样硬化疾病风险相关，是一种动脉粥样硬化风险生物标志物。本研究旨在探讨 MLT 对动脉粥样硬化过程中 Lp-PLA2 表达的影响，并探讨其潜在机制。在体内，apoE 小鼠给予高脂肪饮食，同时给予或不给予 MLT 治疗，然后评估斑块面积和胶原含量。用 MLT 预处理巨噬细胞，然后与 ox-LDL 一起测量铁死亡相关蛋白、NRF2 激活、线粒体功能和氧化应激的水平。MLT 治疗显著减轻了动脉粥样硬化斑块的进展，表现为斑块面积减小和胶原增加。与高脂肪饮食（HD）组相比，MLT 组动脉粥样硬化根部巨噬细胞中的谷胱甘肽过氧化物酶 4（GPX4）和 SLC7A11（xCT，胱氨酸/谷氨酸转运体）水平显著升高。在体外，MLT 激活了核因子-E2 相关因子 2（NRF2）/SLC7A11/GPX4 信号通路，增强了抗氧化能力，同时减少了脂质过氧化作用，并抑制了巨噬细胞中的 Lp-PLA2 表达。此外，MLT 用铁抑素 1（一种铁死亡抑制剂）和/或 erastin（一种铁死亡激活剂）逆转了 ox-LDL 诱导的铁死亡。此外，在 ML385（一种特异性 NRF2 抑制剂）处理的巨噬细胞和 AAV-sh-NRF2 处理的 apoE 小鼠中，MLT 对 Lp-PLA2 表达、抗氧化能力、脂质过氧化和铁死亡的保护作用降低。MLT 通过抑制巨噬细胞铁死亡和部分激活 NRF2 通路来抑制 Lp-PLA2 表达和动脉粥样硬化进程。
