title: Evodiamine represses hypoxia-induced inflammatory proteins expression and hypoxia-inducible factor 1alpha accumulation in RAW264.7.
abstract: Inflammation and low oxygen diffusion are recognized characteristics of cardiovascular diseases such as atherosclerosis. Evodiamine, extracted from the traditional Chinese herb, Evodia rutaecarpa, is a bioactive anti-inflammatory alkaloid. The objective of this study was to investigate whether evodiamine could repress hypoxia-induced inflammatory response. We showed that evodiamine repressed not only COX-2 and iNOS expression but also prostaglandin E2 release in a concentration-dependent manner under hypoxic conditions. Furthermore, our studies indicated that COX-2 mRNA was inhibited by evodiamine, implying that transcriptional activity is involved in the mechanistic pathway. It is striking that hypoxia-inducible factor 1alpha (HIF-1alpha) inhibitor, camptothecin, suppressed hypoxia-induced COX-2 expression rather than pyrrolidine dithiocarbamate, a nuclear factor kappaB inhibitor. In addition, our studies have confirmed that evodiamine inhibited HIF-1alpha, which accounted for the transcriptional activity of COX-2, rather than nuclear factor kappaB in RAW264.7 cells. Finally, evodiamine did not affect either the level of HIF-1alpha mRNA or the degradation rate of HIF-1alpha protein, but it regulated the translational process of HIF-1alpha. We found that hypoxia-evoked phosphorylation of Akt and p70S6K was blocked after evodiamine treatment, in addition to the inhibition of phosphorylation of 4E-BP. These results suggest that the mechanism of repression of hypoxia-induced COX-2 expression by evodiamine is through the inhibition of HIF-1alpha at the translational level and is primarily mediated via dephosphorylation of Akt and p70S6K. Therefore, evodiamine could be an effective therapeutic agent against inflammatory diseases involving hypoxia.
authors.affiliation: Phamacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Nan
authors.initials: YN
authors.lastname: Liu
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Cho-Hwa
authors.initials: CH
authors.lastname: Liao
authors.forename: Der-Yi
authors.initials: DY
authors.lastname: Huang
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.forename: Chieh-Yu
authors.initials: CY
authors.lastname: Peng
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D010936:Plant Extracts; D011759:Pyrrolidines; D011799:Quinazolines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; C049639:evodiamine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D015232:Dinoprostone; D002166:Camptothecin