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

ABSTRACT 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.