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.