Eicosapentaenoic acid (EPA) limits the more rapid oxidation of lipoprotein(a) [Lp(a)] compared with other ApoB particles

Aims Elevated Lp(a) levels increase cardiovascular (CV) risk. Lp(a) contains oxidized phospholipids that may promote lipid oxidation more than other lipoproteins. The highly unsaturated omega˗3 fatty acid EPA has multiple double bonds that can trap free radicals in resonance structures. Purified ethyl-EPA reduced CV events in high-risk patients with elevated Lp(a) despite Lp(a)-associated risk elevation. Since Lp(a) is enriched in oxidized lipids, we hypothesized that Lp(a)-enriched plasma undergoes more rapid oxidation than other ApoB-containing particles, and that EPA limits oxidation of Lp(a)-enriched plasma more effectively than less-unsaturated fatty acids or other lipid lowering treatments. This property could limit the cellular stress responses in endothelial cells. Methods and Results Lp(a) was enriched to >50% total ApoB content to resemble an Lp(a)-associated “high risk” phenotype and compared with matching levels of small-dense LDL (sdLDL) and VLDL by isopycnic centrifugation. Samples were then incubated ± EPA (50 µM) at 37°C for 30 min. Oxidation was initiated with copper sulfate and monitored by malondialdehyde formation. We also subjected EPA to oxidation before measuring its antioxidant activity as compared with other long chain, less saturated fatty acids and lipid lowering agents. Human umbilical vein ECs (HUVECs) were incubated with Lp(a)-enriched plasma following oxidation in the absence and presence of EPA. Cell lysate samples were then analyzed by global LC/MS-based proteomics for significant changes in protein expression (>1-fold). Lp(a)-enriched plasma contained the highest baseline oxidized lipid (p<0.05) and underwent the most rapid oxidation. EPA, but neither the less unsaturated fatty acids nor lipid agents attenuated oxidation of each fraction through 4 hours (p<0.01). Oxidized EPA had diminished antioxidant capacity corresponding to the extent of oxidation. Attenuation of Lp(a) oxidation with EPA also mitigated pro-inflammatory and cellular stress response changes in protein expression. Conclusions Lp(a)-enriched plasma underwent more rapid oxidation than other ApoB-containing lipoproteins and promoted inflammatory changes in EC protein expression, a process attenuated by EPA. This action may contribute to reduced CV risk by EPA in those with elevated Lp(a) levels.