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.
MeSH terms
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Activating Transcription Factor 6 / genetics
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Activating Transcription Factor 6 / metabolism
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Animals
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Aorta / drug effects*
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Aorta / metabolism
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Aorta / pathology
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Apolipoproteins E / deficiency*
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Apolipoproteins E / genetics
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Apoptosis / drug effects
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Atherosclerosis / drug therapy*
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Atherosclerosis / etiology
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Atherosclerosis / genetics
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Atherosclerosis / pathology
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Cholesterol, HDL / blood
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Cholesterol, LDL / blood
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Diet, High-Fat / adverse effects
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Disease Models, Animal
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress / drug effects*
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Equol / pharmacology*
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Eukaryotic Initiation Factor-2 / genetics
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Eukaryotic Initiation Factor-2 / metabolism
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Gene Expression Regulation
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Liver / drug effects
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Liver / metabolism
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Mice
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Mice, Knockout
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NF-E2-Related Factor 2 / agonists
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NF-E2-Related Factor 2 / genetics*
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NF-E2-Related Factor 2 / metabolism
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Palmitic Acid / pharmacology
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Phytoestrogens / pharmacology*
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Signal Transduction
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Thapsigargin / pharmacology
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism
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Triglycerides / blood
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism
Substances
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Activating Transcription Factor 6
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Apolipoproteins E
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Atf6 protein, mouse
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Cholesterol, HDL
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Cholesterol, LDL
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Ddit3 protein, mouse
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Endoplasmic Reticulum Chaperone BiP
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Eukaryotic Initiation Factor-2
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Phytoestrogens
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Triglycerides
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Transcription Factor CHOP
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Palmitic Acid
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Equol
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Thapsigargin
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PERK kinase
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eIF-2 Kinase
Grants and funding
This work was supported by The National Natural Science Foundation of China (No. 81102129; No. 81072288). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.