Equol Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice by Inhibiting Endoplasmic Reticulum Stress via Activation of Nrf2 in Endothelial Cells

Abstract

The development of atherosclerosis is closely related to excessive endoplasmic reticulum stress (ERs). Equol reportedly protects against cardiovascular disease; however, the underlying mechanism for this protection remains unknown. Herein, the mechanisms contributing to the atheroprotective effect of equol were addressed using apolipoprotein E knockout (apoE-/-) mice fed a high-fat diet (HFD) with or without equol. Equol intervention reduced atherosclerotic lesions in the aorta in HFD-fed apoE-/- mice. Plasma lipid analysis showed that equol intervention reduced triglycerides, total cholesterol and LDL-cholesterol and increased HDL-cholesterol. Additionally, equol administration decreased lipid accumulation in the liver. Simultaneously, equol treatment inhibited cell apoptosis induced by t-BHP and thapsigargin in human umbilical vein endothelial cells (HUVECs). Furthermore, equol treatment attenuated palmitate, t-BHP or thapsigargin-induced upregulation of ER stress markers, including p-PERK, p-eIF2α, GRP78, ATF6 and CHOP proteins expression. The same tendency was also observed in aortic lysates in apoE-/- mice fed with equol plus HFD compared with HFD alone. Moreover, equol treatment dose dependently activated the Nrf2 signaling pathway under oxidative stress. Additionally, elevation of Nrf2 induction was found in aortic lysates in apoE-/- mice fed with a HFD diet containing equol compared with a HFD diet without equol. Importantly, Nrf2 siRNA interference induced CHOP and attenuated the effect of equol to inhibit t-BHP mediated CHOP induction, furthermore, abrogated cell apoptosis induced by t-BHP, suggesting a role for Nrf2 in the protective effect of equol in HUVECs. Collectively, these findings implicate that the improvement of atherosclerosis by equol through attenuation of ER stress is mediated, at least in part, by activating the Nrf2 signaling pathway.

Dihydromyricetin inhibits NLRP3 inflammasome‐dependent pyroptosis by activating the Nrf2 signaling pathway in vascular endothelial cells

“…On the other hand, Nrf2 signaling pathway is the main antioxidant response element pathway and studies has affirmed that Nrf2 could be activated by DHM [24,55]; therefore, modulation of the Nrf2 signaling pathway may be a potential mechanism underlying the protective effects promoted by the intake of DHM. Nrf2 signaling pathway regulates the cellular redox homoeostasis and cytoprotective responses, allowing adaptation and survival under conditions of stress, which could be triggered by different treatments inducing ROS formation and antioxidants such as DHM [55] and S-(-)Equol [56]. According to the previous reports, the regulation of PA on Nrf2 signaling is closely related to the processing time and its concentration, and these ROS inducers including PA, H 2 O 2 , UVB, and LPS etc could contribute to cell survival by inducing Nrf2 activation under short time and low level treatment conditions, while excessive exposure to these inducers would inhibit Nrf2 signaling and thus trigger death.…”

Hydrogen Sulfide Inhibits Cigarette Smoke-Induced Endoplasmic Reticulum Stress and Apoptosis in Bronchial Epithelial Cells

“…ERS can activate many signal pathways, PERK-eIF2α-ATF4 signaling pathway (He et al, 2016 ), PI3K-Akt-NOS pathway (Alexaki et al, 2004 ), PERK-eIF2α-CHOP signaling (Gu et al, 2017 ), IRE1α-ASK1-JNK pathway (Kong et al, 2017 ), and IRE1α-ASK1-P38 pathway (Kong et al, 2017 ) have been confirmed to be involved in ERS mediated apoptosis. And Nrf2, plays an important role in oxidative stress, also involved in ERS-mediated apoptosis (Zhang et al, 2016 ; Wang et al, 2017 ). H 2 S has been confirmed to inhibit oxidative stress and inflammation, and relevant signal pathways have crosstalk with these above signals.…”

The roles of gut microbiota and circadian rhythm in the cardiovascular protective effects of polyphenols

“…Equol is more bioactive than daidzein in terms of anti‐oestrogenic activity, antioxidant capacity, and anti‐cancer effects (Arques, Rodriguez, Langa, Landete, & Medina, ). Equol treatment in ApoE −/− mice fed with high‐fat diet (HFD) reduces atherosclerotic lesions in the aorta, reduces triglycerides, total cholesterol, and LDL cholesterol, and increases HDL cholesterol (Zhang et al, ).…”