(CCSP122) AN INCREASED RATIO OF EICOSAPENTAENOIC ACID (EPA) TO ARACHIDONIC ACID (EPA/AA) REDUCED INFLAMMATORY CHANGES IN VASCULAR ENDOTHELIUM

Background: Cardiovascular (CV) risk can be correlated to reduced levels of circulating EPA/AA ratios. A highly purified EPA formulation, icosapent ethyl (IPE), reduced a composite of CV events in high-risk patients in relation to on-treatment EPA levels (REDUCE-IT). These benefits of IPE treatment may result from reduced vascular endothelial dysfunction during inflammation. We measured the effect of EPA on release of soluble intercellular adhesion molecule-1 (sICAM-1) and changes in the EPA/AA ratio in vascular endothelial cells during inflammation.

METHODS AND RESULTS: Human vascular endothelial cells (HUVECs) were challenged with IL-6 (12 ng/mL) for 2 hours and then treated with EPA (40 µM) or vehicle for 24 hours. Total fatty acids were extracted and derivatized using methanol containing 14% boron trifluoride to form fatty acid methyl esters (FAME). Gas chromatography measured total fatty acid content from C14-C24 and normalized to total protein. Levels of sICAM-1 were measured using immunochemistry. Results showed EPA treatment increased the EPA/AA ratio by >20-fold compared to IL-6 treatment alone (1.55 ± 0.11 vs. 0.07 ± 0.003, p< 0.001). The increased EPA/AA ratio correlated with EPA and docosapentaenoic acid (DPA) levels in lysates, which increased by 19-fold (26.71 ± 1.28 vs. 1.28 ± 0.05 mg/g protein, p< 0.001) and 4-fold (29.42 ± 1.91 vs. 6.17 ± 0.36 mg/g protein, p< 0.001), respectively, compared to IL-6. EPA reduced sICAM-1 release by 39% (p < 0.001) following exposure to IL-6.

Conclusion: In vascular ECs, EPA increased the EPA/AA ratio under conditions of inflammation that correlated with reductions in sICAM-1. As on-treatment EPA levels predict reduced CV risk, these changes in fatty acid content in vascular endothelial cells may contribute to the clinical benefits of IPE treatment.