Abstract
Oxidative stress-mediated endothelial injury is considered to be involved in the pathogenesis of various cardiovascular diseases. Farrerol, a typical natural flavanone from the medicinal plant Rhododendron dauricum L., has been reported to show protective effects against oxidative stress-induced endothelial injuries in our previous study. However, its action molecular mechanisms and targets are still unclear. In the present study, we determined whether farrerol can interact with glycogen synthase kinase 3β- (GSK-3β-) nuclear factor erythroid 2-related factor 2- (Nrf2-) antioxidant response element (ARE) signaling, which is critical in defense against oxidative stress. Our results demonstrated that farrerol could specifically target Nrf2 negative regulator GSK-3β and inhibit its kinase activity. Mechanistic studies proved that farrerol could induce an inhibitory phosphorylation of GSK-3β at Ser9 without affecting the expression level of total GSK-3β protein and promote the nuclear translocation of Nrf2 as well as the mRNA and protein expression of its downstream target genes heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) in EA.hy926 cells. Further studies performed with GSK-3β siRNA and specific inhibitor lithium chloride (LiCl) confirmed that GSK-3β inhibition was involved in farrerol-mediated endothelial protection and Nrf2 signaling activation. Moreover, molecular docking and molecular dynamics studies revealed that farrerol could bind to the ATP pocket of GSK-3β, which is consistent with the ATP-competitive kinetic behavior. Collectively, our results firstly demonstrate that farrerol could attenuate endothelial oxidative stress by specifically targeting GSK-3β and further activating the Nrf2-ARE signaling pathway.
Highlights
Cardiovascular diseases are widely recognized as the major cause of disability and mortality [1]
Since farrerol could markedly attenuate H2O2-induced intracellular reactive oxygen species (ROS) production in EA.hy926 cells [19], the ability of farrerol to stimulate the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) was examined by Western blot analysis
Suppressed farrerol-induced upregulation of HO-1 and NQO1. These results demonstrate that farrerol-induced cytoprotective effect and expression of HO-1 and NQO1 are mediated by the activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) in EA.hy926 cells
Summary
Cardiovascular diseases are widely recognized as the major cause of disability and mortality [1]. Growing evidence reveals oxidative stress accounts for a significant proportion of the endothelial function impairment in cardiovascular diseases [4]. Excessive production of reactive oxygen species (ROS) disturbs the balance between oxidant and antioxidant intracellular systems and leads to endothelial cell dysfunction and apoptosis or necrosis. It is thought that protecting endothelial cells against oxidative stress could be beneficial for preventing cardiovascular diseases and could aid in the treatment. Epidemiological and mechanistic studies have indicated that dietary intake of flavonoids is associated with a reduced risk for cardiovascular disease and the biological activities of flavonoids are related to their antioxidative effects [5,6,7]. As the major flavonoids found in citrus fruits and juices, flavanones contribute substantially
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
