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  • Title: Calcium- and phosphatidylinositol 3-kinase/Akt-dependent activation of endothelial nitric oxide synthase by apigenin.
    Author: Chen CC, Ke WH, Ceng LH, Hsieh CW, Wung BS.
    Journal: Life Sci; 2010 Dec 18; 87(23-26):743-9. PubMed ID: 21034748.
    Abstract:
    AIMS: The generation of NO by endothelial nitric oxide synthase (eNOS) plays a major role in maintaining cardiovascular homeostasis. The objective of our present study was to investigate the effects of the flavone compound, apigenin, on eNOS activity and elucidate the molecular mechanisms underlying these effects in endothelial cells (ECs). MAIN METHODS: Bovine artery endothelial cells (BAECs) were exposed in a serum-free medium to apigenin. Cell viability was measured using an Alamar blue assay. The production of intracellular NO was determined using DAF-2/DA. The level of protein was examined by Western blotting. The intracellular Ca(2+) was measured using a fluorescent dye, Fura 2-AM. KEY FINDINGS: Apigenin significantly induced NO production after 6h of treatment. This production was inhibited by pretreatment with the eNOS inhibitor, N(ω)-nitro l-arginine methyl ester (L-NAME). However, treatment with apigenin did not alter the eNOS protein levels but induced a sustained activation of eNOS Ser(1179) phosphorylation. Apigenin was further found to activate ERK1/2, JNK and Akt over various time courses in ECs. Treatment with specific PI3-kinase inhibitors significantly inhibited the increases in NO production and phosphorylation. In contrast, the inhibition of (ERK)1/2, JNK and p38 had no influence on NO production. In addition, apigenin stimulates an increase in the cytosolic Ca(2+) concentration. Apigenin-induced eNOS Ser(1179) phosphorylation and NO production are calcium-dependent, as pretreatment with extracellular or intracellular Ca(2+) chelators inhibits these processes. SIGNIFICANCE: Apigenin-induced calcium-dependent activation of eNOS is primarily mediated via phosphatidylinositol 3-kinase- and Akt pathways, and occurs independently of the eNOS protein content.
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