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Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes
Author(s) -
Zhang Ye,
Wang Gaoyuan,
Wang Taorong,
Cao Wei,
Zhang Lixia,
Chen Xiaoyu
Publication year - 2019
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.14196
Subject(s) - keap1 , oxidative stress , chemistry , apoptosis , reactive oxygen species , microbiology and biotechnology , malondialdehyde , signal transduction , resveratrol , biochemistry , biology , transcription factor , gene
Resveratrol (Res) is a polyphenolic compound that has a variety of biological functions and activities. This study aimed to explore the mechanisms of the antioxidant and proapoptotic effects of Res in H 2 O 2 ‐treated rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLSs) by the Nrf2–Keap1 signaling pathway. We found that 5 µM H 2 O 2 promoted cell proliferation and increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content in RA‐FLSs. However, Res could reverse these effects in 5 µMH2O2‐treated RA‐FLSs by (1) promoting expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1), (2) reducing expression of Kelch‐like ECH–related protein 1 (Keap1), (3) inhibiting production of ROS and MDA, (4) blocking activation of nuclear factor‐κB (NF‐κB) p65, (5) inhibiting cell proliferation and migration, and (6) activating Bcl‐2/Bax to induce apoptosis. After lentiviral silencing of Nrf2 (siNrf2) mRNA expression in RA‐FLSs, Res addition did not increase the expression of Nrf2 or HO‐1 to reduce the production of mitochondrial ROS caused by 5 µM H 2 O 2 . Res reduced the Bcl‐2/Bax ratio, but siNrf2 reduced the ability of Res to promote apoptosis. We conclude that Res inhibits ROS production by activating the Nrf2 pathway, thereby inhibiting activation of NF‐κB and proliferation and migration of RA‐FLSs, to induce apoptosis. Targeting the Nrf2–Keap1 pathway may be a relevant aim of using Res in the treatment of RA.