Mito-Tempo alleviates ox-LDL-provoked foam cell formation by regulating Nrf2/NLRP3 signaling

• Published in: Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2024-06, Vol.88 (7), p.759-767
• Main Authors: Huang, Zhenyu, Zhou, Zhaoli, Ma, Ying, Hu, Yao-Min
• Format: Article
• Language: English
• Subjects: Animals; CD36 Antigens - metabolism; Cyclic N-Oxides - pharmacology; Foam Cells - drug effects; Foam Cells - metabolism; Humans; Inflammasomes - drug effects; Inflammasomes - metabolism; Lipoproteins, LDL - metabolism; Mice; NF-E2-Related Factor 2 - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Organophosphorus Compounds; Piperidines; Pyroptosis - drug effects; RAW 264.7 Cells; Signal Transduction - drug effects
• ISSN: 1347-6947; 1347-6947
• DOI: 10.1093/bbb/zbae058

Our previous studies have demonstrated that Mito-Tempol (also known as 4-hydroxy-Tempo), a mitochondrial reactive oxygen species scavenger, alleviates oxidized low-density lipoprotein (ox-LDL)-triggered foam cell formation. Given the effect of oxidative stress on activating the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, which promotes foam cell formation, we aimed to explore whether Mito-Tempo inhibits ox-LDL-triggered foam cell formation by regulating NLRP3 inflammasome. The results revealed that Mito-Tempo re-activated Nrf2 and alleviated macrophage foam cell formation induced by ox-LDL, whereas the effects were reversed by ML385 (a specific Nrf2 inhibitor). Mito-Tempo restored the expression and nuclear translocation of Nrf2 by decreasing ox-LDL-induced ubiquitination. Furthermore, Mito-Tempo suppressed ox-LDL-triggered NLRP3 inflammasome activation and subsequent pyroptosis, whereas the changes were blocked by ML385. Mito-Tempo decreased lipoprotein uptake by inhibiting CD36 expression and suppressed foam cell formation by regulating the NLRP3 inflammasome. Taken together, Mito-Tempo exhibits potent anti-atherosclerotic effects by regulating Nrf2/NLRP3 signaling.