Nrf2-Keap1 pathway-mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide-treated rheumatoid arthritis fibroblast-like synoviocytes.

Abstract

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 H2 O2 -treated rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) by the Nrf2-Keap1 signaling pathway. We found that 5µM H2 O2 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 5µM H2 O2 . 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.