Fisetin induces Nrf2‐mediated HO‐1 expression through PKC‐δ and p38 in human umbilical vein endothelial cells

Fisetin is a natural flavonoid from fruits and vegetables that exhibits antioxidant, neurotrophic, anti‐inflammatory, and anti‐cancer effects in various disease models. Up‐regulation of heme oxygenase‐1 (HO‐1) expression protects against oxidative stress‐induced cell death, and therefore, plays a crucial role in cytoprotection in a variety of pathological models. In the present study, we investigated the effect of fisetin on the up‐regulation of HO‐1 in human umbilical vein endothelial cells (HUVECs). Small interfering RNA and pharmacological inhibitors of PKC‐δ and p38 MAPK attenuated HO‐1 induction in fisetin‐stimulated HUVECs. Fisetin treatment resulted in significantly increased NF‐E2‐related factor 2 (Nrf2) nuclear translocation, and antioxidant response element (ARE)‐luciferase activity, leading to up‐regulation of HO‐1 expression. In addition, fisetin pretreatment reduced hydrogen peroxide (H 2 O 2 )‐induced cell death, and this effect was reversed by ZnPP, an inhibitor of HO‐1. In summary, these findings suggest that induction of HO‐1 expression via Nrf2 activation may contribute to the cytoprotection exerted by fisetin against H 2 O 2 ‐induced oxidative stress in HUVECs. J. Cell. Biochem. 112: 2352–2360, 2011.