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Biochemical and Molecular Actions of Nutrients

(-)Epigallocatechin Gallate and Quercetin Enhance Survival Signaling in Response to Oxidant-Induced Human Endothelial Apoptosis¹

Division of Life Sciences and Silver Biotechnology Research Center, Hallym University, Chuncheon, Korea

²To whom correspondence should be addressed. E-mail: yhkang{at}hallym.ac.kr.

We reported recently that (-)epigallocatechin gallate and quercetin inhibited H₂O₂-induced apoptosis through modulation of the expression of apoptosis-related Bcl-2 and Bax in endothelial cells. This study attempted to identify possible regulatory sites and mechanisms of antiapoptotic flavonoids, focusing on ROS-mediated signaling in HUVEC. The effects of apigenin on the signaling pathway downstream were compared. Submillimolar H₂O₂ caused >30% cell killing with intracellular oxidant generation. H₂O₂-induced oxidant generation markedly decreased total intracellular glutathione (GSH) levels. Micromolar (-)epigallocatechin gallate and quercetin partially eliminated the dichlorodihydrofluorescein (DCF) and phospho-p53 staining, suggesting that these flavonoids inhibited the accumulation of intracellular oxidants and nuclear transactivation of p53 in H₂O₂-exposed cells. In contrast, cells treated with apigenin remained DCF and phospho-p53 staining positive in response to H₂O₂. (-)Epigallocatechin gallate significantly raised the total GSH level that had been depleted by H₂O₂. Caspase-3 activity was enhanced by H₂O₂, and this increase was inhibited by (-)epigallocatechin gallate and quercetin. Additionally, the upregulation of caspase-3 activation was reversed by these flavonoids at 10 µmol/L; these inhibitory effects were dose dependent. Western blot data revealed that H₂O₂ upregulated phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), which was rapidly reversed by quercetin within 30 min; H₂O₂ activation of c-Jun was downregulated. (-)Epigallocatechin gallate inhibited H₂O₂-induced phosphorylation of JNK and p38 MAPK after 60 min. These results reveal that quercetin blocks JNK- and p38 MAPK-related signaling triggered by the oxidant and may regulate expression of apoptotic downstream genes, preventing apoptosis and promoting cell survival. (-)Epigallocatechin gallate may function as an antiapoptotic agent through other antiapoptotic pathways.

KEY WORDS: • flavonoids • apoptosis • H₂O₂ • survival signaling

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