Lunasin attenuates oxidant‐induced endothelial injury and inhibits atherosclerotic plaque progression in ApoE^−/−mice by up‐regulating heme oxygenase‐1viaPI3K/Akt/Nrf2/ARE pathway

Abstract

Oxidative stress–induced vascular endothelial cell (VEC) injury is a major mechanism in the initiation and development of atherosclerosis. Lunasin, a soybean‐derived 43‐aa peptide, has been previously shown to possess potent antioxidant and anti‐inflammatory activities other than its established anticancer activities. This study investigated the effects of lunasin on protecting VECs from oxidative damage and inhibiting atherosclerotic plaque progression in apolipoprotein E–deficient (ApoE−/−) mice and explored its underlying mechanism. Biochemical and histologic analyses were performed by using EA.hy926 human VECs and a high‐fat diet (HFD) ApoE−/− mouse atherosclerosis model. Our data indicated that lunasin attenuated H2O2‐induced, mitochondria‐dependent endothelial apoptosis via down‐regulating Bax and up‐regulating Bcl‐2, inhibiting the mitochondrial depolarization, and reducing the release of cytochrome c, as well as decreasing the activation of casρase‐9 and caspase‐3 in vitro and in vivo. Mechanic studies showed that lunasin significantly up‐regulated heme oxygenase‐1 via the PI3K/Akt/nuclear factor erythroid 2–related factor 2/antioxidant response element pathway, and reduced H2O2‐induced ROS production in VECs, thereby attenuating oxidant‐induced endothelial injury and inhibiting atherosclerotic plaque progression in ApoE−/− mice. In conclusion, our in vitro and in vivo data suggest that lunasin protects VECs from oxidative damage by enhancing heme oxygenase‐1 expression via activation of the PI3K/Akt/ nuclear factor erythroid 2–related factor 2/antioxidant response element pathway and inhibiting mitochondria‐dependent apoptosis, thereby effectively attenuating atherosclerosis in HFD‐fed ApoE−/− mice. Lunasin may act as a potential therapeutic agent for the prevention and treatment of atherosclerosis.—Gu, L., Ye, P., Li, H., Wang, Y., Xu, Y., Tian, Q., Lei, G., Zhao, C., Gao, Z., Zhao, W., Tan, S. Lunasin attenuates oxidant‐induced endothelial injury and inhibits atherosclerotic plaque progression in ApoE−/− mice by up‐regulating heme oxygenase‐1 via PI3K/Akt/ Nrf2/ARE pathway. FASEB J. 33, 4836–4850 (2019). http://www.fasebj.org

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Role of PI3K in the Progression and Regression of Atherosclerosis

“…Activation of PI3K/Akt and up-regulation of heme oxygenase-1 (HO-1) might be new targets for inhibiting ox-LDL-induced apoptosis. Lunasin (Figure 1) is upregulated through the PI3K/Akt/Nrf2/antioxidant response element (ARE) pathway, and HO-1, attenuated oxidative-induced endothelial injury and inhibits the progression of atherosclerotic plaques in ApoE −/− mice (Gu et al, 2019). Clinical trials have shown that the PI3K/Akt/Nrf2 signaling pathway plays an important role in cardiovascular cell antioxidants mediated by the metabolite S-(-) equol, which is derived from soybean isoflavones (Zhang et al, 2013).…”

Gentiopicroside Ameliorates Oxidative Stress and Lipid Accumulation through Nuclear Factor Erythroid 2-Related Factor 2 Activation

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