Differential suppression of intracellular reactive oxygen species-mediated signaling pathway in vascular endothelial cells by several subclasses of flavonoids.

Increased intracellular reactive oxygen species (ROS) is crucial for vascular endothelial dysfunction, a key step in the initiating of atherosclerosis (AS). The antioxidant activity of flavonoids has been suggested to contribute to AS prevention. However, The association of the structure characteristics to antioxidant capacities in relation to the inhibitory effects on endothelial dysfunction has not been well established. In this study, four subclasses of flavonoids with similar structures, including two anthocyanins (delphinidin and cyanidin), two flavonols (myricetin and quercetin), two flavones (luteolin and apigenin) and two isoflavones (genistein and daidzein) were examined for their inhibitory effects on intracellular ROS-mediated signaling pathway in the human umbilical vein endothelial cell EA.hy926. Cells were pretreated with different flavonoids for 2 h and then exposed to oxLDL of 100 μg/ml for another 24 h. It was found that treatment with different flavonoids alone had no notable effects on cell viability. However, the oxLDL-induced decrease of cell viability, generation of O(2)(·-) and ROS, p38MAPK activation, NF-κB nuclear translocation, NF-κB-modulated transcriptional activity as well as the mRNA expression of genes including ICAM-1, VCAM-1, E-selectin, MMP-1, MMP-2 and MMP-9 were notably inhibited by the pretreatment of different flavonoids through blunting ROS-triggered signaling pathway, in spite of apparent differences. And the number of hydroxyl groups in total, 3',4'-ortho-dihydroxyl in B-ring and 3-hydroxyl group in C-ring of flavonoids were important structure characteristics for the inhibitory effects. Thus, anthocyanins and flavonols such as delphinidin and myricetin exert higher ROS scavenging activities and more significant endothelium-protective effects compared to the other compounds. Our results provide evidence for AS prevention and a basis for designing the potent anti-atherosclerotic agents.

Yi L ，Chen CY ，Jin X ，Zhang T ，Zhou Y ，Zhang QY ，Zhu JD ，Mi MT ... -  《-》

Isorhamnetin prevent endothelial cell injuries from oxidized LDL via activation of p38MAPK.

Bao M ，Lou Y 《EUROPEAN JOURNAL OF PHARMACOLOGY》

Inhibitory effect of delphinidin on monocyte-endothelial cell adhesion induced by oxidized low-density lipoprotein via ROS/p38MAPK/NF-κB pathway.

Chen CY ，Yi L ，Jin X ，Zhang T ，Fu YJ ，Zhu JD ，Mi MT ，Zhang QY ，Ling WH ，Yu B ... -  《-》

Morin modulates the oxidative stress-induced NF-kappaB pathway through its anti-oxidant activity.

Kim JM ，Lee EK ，Park G ，Kim MK ，Yokozawa T ，Yu BP ，Chung HY ... -  《-》

Hydroxytyrosol reduces intracellular reactive oxygen species levels in vascular endothelial cells by upregulating catalase expression through the AMPK-FOXO3a pathway.

Reactive oxygen species are critically involved in the endothelial dysfunction that contributes to atherosclerosis development. Hydroxytyrosol (HT), a main phenolic compound in olive oil and leaves from Olea europaea L., has antiatherogenic properties with powerful antioxidant activity. The present study verifies the antioxidant activity of HT on H2O2-induced intracellular reactive oxygen species in porcine pulmonary artery endothelial cells (VECs) and the involved molecular mechanisms. Incubation of VECs with HT prevented the increase in intracellular reactive oxygen species levels in the presence of H2O2. HT increased catalase mRNA, protein and activity. Catalase siRNA suppressed HT-dependent reduction of intracellular reactive oxygen species. HT increased both cytosolic and nuclear protein levels of forkhead transcription factor 3a (FOXO3a), as well as the phosphorylation of AMP-activated protein kinase (AMPK) that translocates FOXO3a to the nucleus. AMPK siRNA and a specific inhibitor suppressed HT-induced FOXO3a upregulation and catalase expression. Moreover, FOXO3a siRNA blocked HT-dependent increase in catalase expression. Taken together, our findings strongly demonstrate that HT positively regulates the antioxidant defense system in VECs by inducing the phosphorylation of AMPK with subsequent activation of FOXO3a and catalase expression, and provides a molecular basis for the prevention of cardiovascular diseases by HT.

Zrelli H ，Matsuoka M ，Kitazaki S ，Zarrouk M ，Miyazaki H ... -  《-》