ADAPTIVE RESPONSE INDUCED BY CYANIDIN-3-O-GLUCOSIDE IN TNF-alfa EXPOSED ENDOTHELIAL CELLS IS MEDIATED BY NRF2 ACTIVATION

Many plant antioxidants, taken through the daily diet or dietary supplements, have been shown able to prevent free radical-related diseases by counteracting cell oxidative stress. However it is now considered that the in vivo beneficial effects of these phytochemicals are unlikely to be explained just by their antioxidant capability. Several plant antioxidants exhibit hormetic properties, by acting as „low-dose stressors‟ that may prepare cells to resist more severe stress. The discovery of specific genes regulated by Antioxidant Responsive Element – ARE (HO-1, NQO1, -GCS) and pathways (Nrf2 mediated adaptive response) affected by antioxidants, led to the hypothesis that some phytochemicals may act as modulators of gene regulatory and signal transduction pathways. Herein, we have investigated the effects of cyanidin-3-O-glucoside (C3G), an anthocyanin belonging to flavonoid family and commonly present in food and vegetables from Mediterranean Diet, on cell signaling pathways involved in endothelial cells adaptive response. At this scope, we used an experimental model with human umbilical vein endothelial cells (HUVECs) challenged with TNF-α. Pretreatment with C3G appeared able to prevent endothelial dysfunction activated by TNF-α and to improve cellular antioxidant systems. Furthermore we demonstrated that Nrf2 transcription factor is involved in the C3G protective effect and that the inhibition of MAP Kinases ERK1/2 is able to reduce the C3G–induced adaptive response in HUVECs. In conclusion, our data support the hypothesis that dietary plants polyphenols (such as C3G) can play an important role in the prevention of diseases associated with oxidative stress, not due to their putative antioxidant properties but through activities and roles totally independent on such capacity and interacting with cell functions at different levels.