Eicosapentaenoic Acid Increases Vascular and Pulmonary Endothelial Ferritin Levels with Enhanced Heme Oxygenase-1 Expression during Inflammation

Abstract

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Amarin Pharma Inc. and Elucida Research LLC. Background/Synopsis Inducible heme oxygenase-1 (HO-1) catalyzes the degradation of heme into biliverdin, carbon monoxide, and ferrous iron. Increased free iron triggers production of intracellular ferritin. Ferritin as well as the other HO-1 products have potent antioxidant, vasodilatory and anti-inflammatory actions. Unlike trials using mixed omega-3 formulations, eicospentaenoic acid (EPA) only treatment (icosapent ethyl) was associated with reduced cardiovascular (CV) events in high-risk patients with elevated triglycerides (REDUCE-IT) but the mechanism is not fully understood. Objective/Purpose This study compared the treatment effects of EPA on protein expression in endothelial cells (ECs) isolated from vein and pulmonary tissue under conditions of inflammation using the cytokine IL-6. Methods Human umbilical vein endothelial cells (HUVECs) and pulmonary microvascular ECs were first challenged with IL-6 (12 ng/mL) for 2 hours, and then treated with EPA (40 micromolar) for 24 hours. Proteomic analysis was performed using LC/MS to measure relative expression levels of >1,000 proteins simultaneously. Only significant (p<0.05) changes in expression between treatment groups >1-fold were included in the analysis. Results Cells treated with EPA significantly down/up-regulated expression of 310/276 and 212/229 proteins in vascular and pulmonary ECs, respectively, compared with IL-6 alone. In particular, EPA increased levels of HO-1 by 220% (p = 7.9E-50) and 190% (p = 2.8E-32) in vascular and pulmonary ECs, respectively. Increased HO-1 expression resulted in increased levels of ferritin light chain by 120% (p = 4.0E10-5) and 110% (p = 0.049) in vascular and pulmonary ECs, respectively, and ferritin heavy chain by 110% (p = 0.0002) and 160% (p = 1.4E10-6), respectively. Conclusions EPA increased expression of HO-1, a protein that has broad atheroprotective benefits, in both vascular and pulmonary ECs that correlated with increased ferritin levels during inflammation. The ability of EPA to enhance cytoprotective proteins has therapeutic implications for patients at risk for CV disease. Nothing to disclose.