Evodiamine represses hypoxia-induced inflammatory proteins expression and hypoxia-inducible factor 1α accumulation in RAW264.7
Journal
Shock
Journal Volume
32
Journal Issue
3
Pages
263-269
Date Issued
2009
Author(s)
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 1α (HIF-1α) inhibitor, camptothecin, suppressed hypoxia-induced COX-2 expression rather than pyrrolidine dithiocarbamate, a nuclear factor κB inhibitor. In addition, our studies have confirmed that evodiamine inhibited HIF-1α, which accounted for the transcriptional activity of COX-2, rather than nuclear factor κB in RAW264.7 cells. Finally, evodiamine did not affect either the level of HIF-1α mRNA or the degradation rate of HIF-1α protein, but it regulated the translational process of HIF-1α. 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-1α 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. ? 2009 The Shock Society.
SDGs
Other Subjects
camptothecin; cyclooxygenase 2; evodiamine; hypoxia inducible factor 1alpha; immunoglobulin enhancer binding protein; inducible nitric oxide synthase; initiation factor 4E binding protein; phosphatidylinositol 3 kinase; prostaglandin E2; protein kinase B; pyrrolidine dithiocarbamate; animal cell; article; controlled study; drug effect; drug inhibition; drug mechanism; enzyme inhibition; hypoxia; inflammation; macrophage; mouse; nonhuman; prostaglandin release; protein dephosphorylation; protein expression; protein function; protein phosphorylation; transcription initiation; translation regulation; Animals; Anti-Inflammatory Agents; Blotting, Western; Camptothecin; Cell Hypoxia; Cell Line; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Phosphorylation; Plant Extracts; Proto-Oncogene Proteins c-akt; Pyrrolidines; Quinazolines; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases, 70-kDa; Thiocarbamates
Type
journal article