EVODIAMINE REPRESSES HYPOXIA-INDUCED INFLAMMATORY PROTEINS EXPRESSION AND HYPOXIA-INDUCIBLE FACTOR 1α ACCUMULATION IN RAW264.7

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 E-2 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 1 alpha (HIF-1 alpha) inhibitor, camptothecin, suppressed hypoxia-induced COX-2 expression rather than pyrrolidine dithiocarbamate, a nuclear factor kappa B inhibitor. In addition, our studies have confirmed that evodiamine inhibited HIF-1 alpha, which accounted for the transcriptional activity of COX-2, rather than nuclear factor kappa B in RAW264.7 cells. Finally, evodiamine did not affect either the level of HIF-1 alpha mRNA or the degradation rate of HIF-1 alpha protein, but it regulated the translational process of HIF-1 alpha. 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-1 alpha 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.