Evodiamine represses hypoxia-induced inflammatory proteins expression and hypoxia-inducible factor 1alpha accumulation in RAW264.7

Shock. 2009 Sep;32(3):263-9. doi: 10.1097/SHK.0b013e31819940cb.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Blotting, Western
  • Camptothecin / pharmacology
  • Cell Hypoxia / physiology*
  • Cell Line
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects*
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / metabolism
  • Phosphorylation / drug effects
  • Plant Extracts / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrrolidines / pharmacology
  • Quinazolines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Thiocarbamates / pharmacology


  • Anti-Inflammatory Agents
  • Enzyme Inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NF-kappa B
  • Plant Extracts
  • Pyrrolidines
  • Quinazolines
  • Thiocarbamates
  • pyrrolidine dithiocarbamic acid
  • evodiamine
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Dinoprostone
  • Camptothecin