MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction

Luo, Xing; Wang, Yuehong; Zhu, Xinxin; Chen, Yuwu; Xu, Biyi; Bai, Xiaoxuan; Weng, Xiuzhu; Xu, Jinmei; Tao, Yangyang; Yang, Dan; Du, Jie; Lv, Ying; Zhang, Shan; Hu, Sining; Li, Ji; Jia, Haibo

doi:10.1016/j.redox.2023.102987

Cited by 11 publications

(1 citation statement)

References 83 publications

(98 reference statements)

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“…Vitamin E supplementation controls iron homeostasis by inhibiting NRF2-mediated iron-responsive gene expression and increasing iron efflux through FPN in the liver [157] . Micheliolide, an aesquiterpene lactone, inhibits atherosclerosis by activating the NRF2 pathway to inhibit ferroptosis in macrophages [158] . Recently, single-cell transcriptomics revealed that, compared with control aortic macrophages, aortic macrophages from Nrf2 -knockout mice exhibit differential changes in subtype-specific transcriptomes associated with inflammation, iron homeostasis, cell damage, and ferroptosis pathways [189] .…”

Section: Ferroptosis Is An Important Potential Treatment Target In Asmentioning

confidence: 99%

Ferroptosis: a potential target for the treatment of atherosclerosis

Li,

Liu,

Xiong

et al. 2024

ABBS

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Atherosclerosis (AS), the main contributor to acute cardiovascular events, such as myocardial infarction and ischemic stroke, is characterized by necrotic core formation and plaque instability induced by cell death. The mechanisms of cell death in AS have recently been identified and elucidated. Ferroptosis, a novel iron-dependent form of cell death, has been proven to participate in atherosclerotic progression by increasing endothelial reactive oxygen species (ROS) levels and lipid peroxidation. Furthermore, accumulated intracellular iron activates various signaling pathways or risk factors for AS, such as abnormal lipid metabolism, oxidative stress, and inflammation, which can eventually lead to the disordered function of macrophages, vascular smooth muscle cells, and vascular endothelial cells. However, the molecular pathways through which ferroptosis affects AS development and progression are not entirely understood. This review systematically summarizes the interactions between AS and ferroptosis and provides a feasible approach for inhibiting AS progression from the perspective of ferroptosis.

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Section: Ferroptosis Is An Important Potential Treatment Target In Asmentioning

confidence: 99%

Ferroptosis: a potential target for the treatment of atherosclerosis

Li,

Liu,

Xiong

et al. 2024

ABBS

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Ginkgo Flavone Aglycone Ameliorates Atherosclerosis via Inhibiting Endothelial Pyroptosis by Activating the Nrf2 Pathway

Chen,

Yang,

Liao

et al. 2024

Phytotherapy Research

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Natural antioxidants have been shown to be effective against atherosclerosis. Ginkgo flavone aglycone (GA) has strong antioxidant properties and can protect against endothelial damage. However, the mechanisms by which GA protects against atherosclerosis remain largely unexplored. This study hopes to find the anti‐atherosclerotic mechanism of GA. ApoE−/− mice fed a high‐fat diet were used for modeling atherosclerosis. The efficacy of GA on mice with atherosclerosis was evaluated based on the following indicators: Oil Red O staining, Masson staining, lipid content, and apoptosis. Transmission electron microscopy, Western blot, immunofluorescence staining, and propidium iodide staining were used to analyze the effects of GA on ox‐LDL‐treated human aortic endothelial cells. GA activated Nrf2 by promoting the nuclear translocation of Nrf2, thereby inhibiting endothelial pyroptosis. GA prevented endothelial pyroptosis suppressed oxidative stress, and inhibited the development of atherosclerosis in ApoE−/− mice fed high‐fat diets. At the cellular level, GA suppressed ox‐LDL‐induced pyroptosis of HAECs by reducing reactive oxygen species (ROS) levels and inhibiting NLRP3 inflammasome. Furthermore, siRNA targeting Nrf2 or ML385, an Nrf2 inhibitor, reversed these effects. GA liberated Nrf2 from Keap1 sequestration, enhanced the nuclear translocation of Nrf2 and the transcription of downstream antioxidant proteins, reinforced the antioxidant defense system, and inhibited oxidative stress, thereby preventing endothelial cell pyroptosis, and attenuating the progression of atherosclerosis. This study indicated that GA mitigated endothelial pyroptosis by modulating Keap1/Nrf2 interactions, shedding light on the potential mechanisms underlying the protective effects of natural antioxidants against atherosclerosis.

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