Brain vascular endothelial cell (EC) dysfunction contributes to ischemic stroke due to inflammation and release of pro-thrombotic factors. Treatment with icosapent ethyl (IPE), the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA), reduced first and total ischemic strokes each by 36%, in statin-treated patients with elevated cardiovascular risk (REDUCE-IT). We tested the effects of EPA on cytokine release and expression of inflammatory proteins from brain microvascular ECs during inflammation.
Methods and Results
Human brain microvascular endothelial cells were pretreated with the cytokine IL-6 at 12 ng/ml for 2 h before treatment with EPA (40 μM) for 24 h. Proteomic analysis was performed using LC/MS to capture relative expression levels. Only significant changes in protein expression between treatment groups >1-fold were analyzed. Levels of soluble intercellular adhesion molecule-1 (sICAM-1) and tumor necrosis factor-α (TNF-α) were measured by immunochemistry (ELISA). IL-6 exposure produced increased levels of sICAM-1 and TNF-α by 102% and 147% (p < 0.001), respectively, in brain ECs compared with vehicle. EPA treatment reduced release of sICAM-1 by 43% (p < 0.001) and TNF-α by 52% (p < 0.001) compared to IL-6 alone. EPA also decreased expression of 43 proteins involved in the “neutrophil degranulation” pathway in brain ECs (p-adjusted = 2.63 × 10-12). EPA also decreased expression of prothrombin by 1.3-fold (p = 2.10 × 10-24) relative to IL-6 alone.
EPA significantly reduced cytokine release and expression of inflammatory and pro-thrombotic proteins in brain ECs during inflammation. The ability of EPA to reverse brain EC dysfunction and inflammation may contribute to reductions in stroke risk, as demonstrated in large outcome trials.
Amarin Pharma Inc., Elucida Research LLC
© 2022 Published by Elsevier Inc.