Cyanidin-3-O-glucoside counters the response to TNF-alpha of endothelial cells by activating Nrf2 pathway

Many dietary phytochemicals have been shown able to prevent a large spectrum of diseases, including cardiovascular disorders, with a mechanism commonly ascribed to an antioxidant effect. However, these in vivo beneficial effects are unlikely to be explained on the base of this mechanism. The discovery of specific genes regulated by the antioxidant responsive element (ARE) affected by antioxidants/electrophiles, led to the hypothesis that some phytochemicals may act as modulators of signal transduction pathways. The aim of the study was to investigate if in vitro pharmacological activation of Nrf2 pathway by cyanidin-3-O-glucoside (C3G) may be involved in its antiatherogenic effects. METHODS AND RESULTS: Herein, we investigated the in vitro effects of C3G on cell signaling pathways in human umbilical vein endothelial cells (HUVECs) challenged with tumor necrosis factor-α (TNF-α). Pretreatment with C3G prevented oxidative stress, improved antioxidant systems, and activated Nrf2/ARE pathway, at baseline and after TNF-α treatment. Furthermore, we demonstrated the involvement of specific mitogen-activated protein kinases (MAPKs) (ERK1/2) in C3G induction of Nrf2/ARE pathway. Finally, the inactivation of ERK1/2 activity by the inhibitor PD98059 abolished the increase of Nrf2 nuclear accumulation induced by C3G, and also increased NF-κB p65 nuclear translocation in TNF-α challenged cells. CONCLUSION: Our data confirm the hypothesis that natural Nrf2 and HO-1 inducers, such as C3G and other dietary phytochemicals, might be a potential therapeutic strategy to protect vascular system against various stressors preventing several pathological conditions.