Department of Epidemiology, Institute of Military Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, P. R. China.
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, P. R. China.
Lipids Health Dis. 2024 Sep 3;23(1):279. doi: 10.1186/s12944-024-02263-1.
NOD-like receptor protein 3 (NLRP3) inflammasome activation is indispensable for atherogenesis. Mitophagy has emerged as a potential strategy to counteract NLRP3 inflammasome activation triggered by impaired mitochondria. Our previous research has indicated that dihydromyricetin, a natural flavonoid, can mitigate NLRP3-mediated endothelial inflammation, suggesting its potential to treat atherosclerosis. However, the precise underlying mechanisms remain elusive. This study sought to investigate whether dihydromyricetin modulates endothelial mitophagy and inhibits NLRP3 inflammasome activation to alleviate atherogenesis, along with the specific mechanisms involved.
Apolipoprotein E-deficient mice on a high-fat diet were administered daily oral gavages of dihydromyricetin for 14 weeks. Blood samples were procured to determine the serum lipid profiles and quantify proinflammatory cytokine concentrations. Aortas were harvested to evaluate atherosclerotic plaque formation and NLRP3 inflammasome activation. Concurrently, in human umbilical vein endothelial cells, Western blotting, flow cytometry, and quantitative real-time PCR were employed to elucidate the mechanistic role of mitophagy in the modulation of NLRP3 inflammasome activation by dihydromyricetin.
Dihydromyricetin administration significantly attenuated NLRP3 inflammasome activation and vascular inflammation in mice on a high-fat diet, thereby exerting a pronounced inhibitory effect on atherogenesis. Both in vivo and in vitro, dihydromyricetin treatment markedly enhanced mitophagy. This enhancement in mitophagy ameliorated the mitochondrial damage instigated by saturated fatty acids, thereby inhibiting the activation and nuclear translocation of NF-κB. Consequently, concomitant reductions in the transcript levels of NLRP3 and interleukin-1β (IL-1β), alongside decreased activation of NLRP3 inflammasome and IL-1β secretion, were discerned. Notably, the inhibitory effects of dihydromyricetin on the activation of NF-κB and subsequently the NLRP3 inflammasome were determined to be, at least in part, contingent upon its capacity to promote mitophagy.
This study suggested that dihydromyricetin may function as a modulator to promote mitophagy, which in turn mitigates NF-κB activity and subsequent NLRP3 inflammasome activation, thereby conferring protection against atherosclerosis.
核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体的激活对于动脉粥样硬化的形成是必不可少的。线粒体自噬已成为一种对抗受损线粒体触发的 NLRP3 炎性小体激活的潜在策略。我们之前的研究表明，二氢杨梅素是一种天然黄酮类化合物，可减轻 NLRP3 介导的内皮炎症，表明其具有治疗动脉粥样硬化的潜力。然而，其确切的潜在机制仍不清楚。本研究旨在探讨二氢杨梅素是否通过调节内皮细胞的线粒体自噬来抑制 NLRP3 炎性小体的激活，从而减轻动脉粥样硬化的发生，并探讨其具体的作用机制。
用高脂饮食喂养载脂蛋白 E 缺陷小鼠，每天口服给予二氢杨梅素灌胃 14 周。采集血液样本以确定血清脂质谱并定量促炎细胞因子的浓度。取主动脉以评估动脉粥样硬化斑块的形成和 NLRP3 炎性小体的激活。同时，在人脐静脉内皮细胞中，采用 Western blot、流式细胞术和实时定量 PCR 来阐明线粒体自噬在二氢杨梅素调节 NLRP3 炎性小体激活中的作用机制。
二氢杨梅素给药可显著抑制高脂饮食小鼠的 NLRP3 炎性小体激活和血管炎症，从而对动脉粥样硬化的发生产生显著的抑制作用。无论是在体内还是在体外，二氢杨梅素治疗均可显著增强线粒体自噬。这种线粒体自噬的增强可改善饱和脂肪酸引起的线粒体损伤，从而抑制 NF-κB 的激活和核转位。结果，观察到 NLRP3 和白细胞介素-1β（IL-1β）的转录水平降低，同时 NLRP3 炎性小体的激活和 IL-1β 的分泌减少。值得注意的是，二氢杨梅素对 NF-κB 的激活以及随后的 NLRP3 炎性小体的抑制作用至少部分依赖于其促进线粒体自噬的能力。
本研究表明，二氢杨梅素可能作为一种调节剂，通过促进线粒体自噬，从而减轻 NF-κB 的活性和随后的 NLRP3 炎性小体的激活，从而对动脉粥样硬化起到保护作用。
