Abstract 4366096: Eicosapentaenoic Acid Attenuates Oxidation of Lp(a) and other Atherogenic Lipoproteins by a Potential Scavenging Mechanism

Abstract

Background: Lipoprotein(a) (Lp(a)) is an ApoB-containing particle, and the primary carrier of oxidized phospholipid linked to increased cardiovascular (CV) risk. The oxPL may induce rapid lipid oxidation compared with other ApoB particles. The omega-3 fatty acid (n-3FA) EPA (20:5) delivered as icosapent ethyl (4 g/d) reduced CV events in high-risk patients, including those with elevated Lp(a) (REDUCE-IT). Hypothesis: We suspect EPA blunts lipid oxidation via the 5 methylene-interrupted alkene bonds on EPA, and this structure favors radical scavenging in lipoprotein particles – including Lp(a) – more than comparable agents at pharmacologic concentrations. Methods: Lp(a), small dense LDL (sdLDL), and TG-rich lipoproteins (VLDL) were enriched to 66% of total ApoB-containing particles (the remaining 34% being LDL) from patients following isopycnic centrifugation. Lp(a), sdLDL, pure LDL, and VLDL were matched for total protein (50 µg/mL) and incubated at 37°C for 30 min in the absence or presence of EPA (50 µM). Samples then underwent copper sulfate-induced oxidation monitored by formation of malondialdehyde (MDA) for 4 h. The antioxidant effects of EPA were then compared with the lipophilic scavenging agent, probucol. We also deliberately oxidized EPA and the n-3FA alpha-linolenic acid (ALA, 18:3) to damage alkene bonds and correlated this with antioxidant activity. Results: Lp(a)-enriched plasma underwent significantly more rapid oxidation than the other fractions (58% of total lipid was oxidized at 0.5 h compared with 28% of sdLDL-enriched, 18% of pure LDL, and 6% VLDL) and EPA attenuated oxidation of all particles >63% at the time peak oxidation levels were reached for each fraction (all p <0.001). At these times, probucol reduced MDA levels 20%, 21%, and 85% in Lp(a), sdLDL, and LDL, respectively (all p <0.05) but not in VLDL. EPA exerted significantly more antioxidant action than ALA when undamaged, while oxidation of EPA and ALA – evidenced by increased lipid oxidation markers – reduced their antioxidant capacity. Conclusions: In Lp(a)-enriched plasma, Lp(a) underwent more rapid oxidation than other ApoB-containing particles. EPA attenuated oxidation of all particles at pharmacologic levels in contrast with other lipid-centric antioxidants tested, which is consistent with a radical scavenging mechanism. The potent inhibition of Lp(a) oxidation by EPA may contribute to the benefit observed in REDUCE-IT, including those subjects with elevated Lp(a) levels.