Estrogen Receptor and PI3K/Akt Signaling Pathway Involvement in S-(-)Equol-Induced Activation of Nrf2/ARE in Endothelial Cells
Open accessAbstract
S-(-)equol, a natural product of the isoflavone daidzein, has been reported to offer cytoprotective effects with respect to the cardiovascular system, but how this occurs is unclear. Interestingly, S-(-)equol is produced by the human gut, suggesting a role in physiological processes. We report that treatment of human umbilical vein endothelial cells and EA.hy926 cells with S-(-)equol induces ARE-luciferase reporter gene activity that is dose and time dependent. S-(-)equol (10-250 nM) increases nuclear factor-erythroid 2-related factor 2 (Nrf2) as well as gene products of Nrf2 target genes heme oxygenase-1 (HO-1) and NAD(P)H (nicotinamide-adenine-dinucleotide-phosphate) quinone oxidoreductase 1 (NQO1). Endothelial cells transfected with an HA-Nrf2 expression plasmid had elevated HA-Nrf2, HO-1, and NQO1 in response to S-(-)equol exposure. S-(-)equol treatment affected Nrf2 mRNA only slightly but significantly increased HO-1 and NQO1 mRNA. The pretreatment of cells with specific ER inhibitors or PI3K/Akt (ICI182,780 and LY294002) increased Nrf2, HO-1, and NQO1 protein, impaired nuclear translocation of HA-Nrf2, and decreased ARE-luciferase activity. Identical experiments were conducted with daidzein, which had effects similar to S-(-)equol. In addition, DPN treatment (an ERβ agonist) induced the ARE-luciferase reporter gene, promoting Nrf2 nuclear translocation. Cell pretreatment with an ERβ antagonist (PHTPP) impaired S-(-)equol-induced Nrf2 activation. Pre-incubation of cells followed by co-treatment with S-(-)equol significantly improved cell survival in response to H2O2 or tBHP and reduced apoptotic and TUNEL-positively-stained cells. Notably, the ability of S-(-)equol to protect against H2O2-induced cell apoptosis was attenuated in cells transfected with an siRNA against Nrf2. Thus, beneficial effects of S-(-)equol with respect to cytoprotective antioxidant gene activation may represent a novel strategy to prevent and treat cardiovascular diseases.
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Other plant-derived compounds, such as equol, are known to stimulate Nrf2 and increase endogenous detoxifying enzymes and antioxidant production.
“In addition to dietary intake of vitamins and supplementation of antioxidant ingredients, other plant-derived compounds, such as equol, are known to stimulate Nfr2 and increase endogenous detoxifying enzymes and antioxidant production [2,73].”
S-equol protected against peroxide-induced endothelial cell apoptosis by activation of estrogen receptor and Nrf2/ARE signaling pathways.
“Zhang et al. (2013) that showed S-equol protected against peroxide-induced endothelial cell apoptosis by activation of estrogen receptor and Nrf2/ARE signaling pathways [73].”
Equol increases nuclear-factor-erythroid 2-related factor 2 (Nrf2) expression.
“equol has been shown to increase nuclear-factor-erythroid 2-related factor 2 (Nrf2) expression [73].”
Equol can increase levels of the master gene Nrf2, which regulates endogenous expression of detoxifying proteins and many other antioxidant enzymes involved in wound repair and protection against skin cancer.
“equol itself is a very strong antioxidant, and, in turn, it can increase the levels of the master gene, Nrf2, which regulates the endogenous expression of detoxifying proteins and many other antioxidant enzymes that are involved in wound repair, protection against skin cancer”
Nrf2 activation guards against dermal damage from sunlight (ionizing radiation) and oxidative stress via ROS.
“where Nrf2 activation guards against dermal damage, from sunlight (ionizing radiation) and oxidative stress via ROS [2,69-73,76,99].”
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References 54 · Cited by 80
- Authors
- Zhang, T., Liang, X., Shi, L., Wang, L., Chen, J., Kang, C., Zhu, J., & Mi, M.
- Affiliations
- Army Medical University (CN)
- Corresponding author
- Mi, Mantian
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-11-19
- Volume
- 8
- Issue
- 11
- Pages
- e79075
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3833998
- OpenAlex
- W2004696317
- Cited by
- 80
- References
- 54
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 10 · 2021: 9 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 8 · 2015: 4 · 2014: 8
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81102129)
- Chongqing Science and Technology Commission (CSTC, 2011AB5040, 2011AB5040)
- Natural Science Foundation of Chongqing
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Pathology and Forensic Medicine › Phytoestrogen effects and research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- ol, Nrf2/ARE pathway, estrogen receptor beta, PI3K/Akt signaling, daidzein, heme oxygenase-1, NQO1, endothelial cells, antioxidant defense, oxidative stress, apoptosis, Nrf2 nuclear translocation, cardioprotection, ERβ agonists, PHTPP
- MeSH terms
- Cardiovascular Diseases, Female, Humans, Hydrogen Peroxide, Male, Signal Transduction, NAD(P)H Dehydrogenase (Quinone), Oxidants, Phosphatidylinositol 3-Kinases, Response Elements, Estrogen Receptor beta, Phytoestrogens, Proto-Oncogene Proteins c-akt, NF-E2-Related Factor 2, Heme Oxygenase-1, Equol, Human Umbilical Vein Endothelial Cells
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