# Eicosapentaenoic acid limits the more rapid oxidation of lipoprotein(a) compared with other apolipoprotein B particles

## TL;DR

Eicosapentaenoic acid (EPA) reduces the rapid oxidation of lipoprotein(a), which may lower cardiovascular risk in people with high Lp(a) levels.

## Contribution

EPA was shown to specifically limit oxidation of Lp(a) compared to other lipoproteins and lipid-lowering treatments.

## Key findings

- Lp(a)-enriched plasma oxidized more rapidly than other ApoB-containing particles.
- EPA significantly attenuated Lp(a) oxidation and reduced inflammatory protein changes in endothelial cells.
- Less unsaturated fatty acids and lipid-lowering agents did not show similar antioxidant effects.

## Abstract

Elevated lipoprotein(a) [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 eicosapentaenoic 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 apolipoprotein B (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 (ECs).

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 very-low-density lipoprotein by isopycnic centrifugation. Samples were then incubated with EPA (50 µM) or equivolume vehicle 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 when 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 analysed by global liquid chromatography-mass spectroscopy (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 h (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.

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.

Graphical AbstractProposed mechanism of antioxidant activity of eicosapentaenoic acid (EPA) in Lp(a). Lp(a)-enriched lipoprotein fractions undergo more rapid lipid oxidation compared with other apolipoprotein B (ApoB)-containing lipoproteins, possibly due to oxidized phospholipids (oxPLs) attached to its unique apo(a) and in the phospholipid monolayer surrounding the insoluble lipid-rich core. The highly unsaturated fatty acid EPA exhibits significant dose- and time-dependent antioxidant activity in Lp(a). This action may arise from the five double bonds along the acyl chain allow for free radical resonance stabilization and may contribute to significant cardiovascular event reduction by highly purified EPA [delivered as icosapent ethyl (IPE)], particularly patients with elevated Lp(a) (REDUCE-IT).

Proposed mechanism of antioxidant activity of eicosapentaenoic acid (EPA) in Lp(a). Lp(a)-enriched lipoprotein fractions undergo more rapid lipid oxidation compared with other apolipoprotein B (ApoB)-containing lipoproteins, possibly due to oxidized phospholipids (oxPLs) attached to its unique apo(a) and in the phospholipid monolayer surrounding the insoluble lipid-rich core. The highly unsaturated fatty acid EPA exhibits significant dose- and time-dependent antioxidant activity in Lp(a). This action may arise from the five double bonds along the acyl chain allow for free radical resonance stabilization and may contribute to significant cardiovascular event reduction by highly purified EPA [delivered as icosapent ethyl (IPE)], particularly patients with elevated Lp(a) (REDUCE-IT).