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Background: Elevated lipoprotein(a) (Lp(a)) levels are causally and independently associated with increased cardiovascular (CV) risk. EPA administered as icosapent ethyl (IPE) reduced CV events in high-risk, statin-treated patients (REDUCE-IT), including those with elevated Lp(a) levels. The mechanism of action may be related to reduced lipoprotein oxidation, including Lp(a), resulting in endothelial cell (EC) stress reduction. Hypothesis: We hypothesized that EPA attenuates Lp(a) oxidation – possibly by scavenging free radicals – leading to reduced EC stress response and related protein expression. Methods: Lp(a) was enriched to >50% of total ApoB-containing (LDL) particles in plasma from patients with elevated levels following isopycnic centrifugation. Lp(a)-enriched fractions were incubated with EPA (Lp(a) + EPA, 50 µM) or equivolume vehicle (Lp(a) + veh) at 37°C for 30 min followed by oxidation with CuSO 4 (20 µM). After 2 h, human umbilical vein ECs (HUVECs) were incubated with Lp(a) + EPA or Lp(a) + veh for 8 h. Cell lysate samples were then analyzed by global LC/MS-based proteomics. Between group protein changes >1-fold and a false discover rate (FDR)-adjusted p <0.05 were considered significant. Lp(a) oxidation levels were characterized by both lipid hydroperoxide (LOOH) formation and malondialdehyde (MDA) using colorimetric assays. Results: EPA significantly attenuated Lp(a)-enriched oxidation through 2 h compared with vehicle-treated control, including 8% and 61% reduction of LOOH and MDA, respectively, both p <0.001. A total of 20 proteins were significantly modulated by Lp(a) + veh relative to control. Among these, Lp(a) + veh induced increased expression of heat shock protein (HSP) 70 kDa (3.8-fold) along with its co-chaperones HSP 105/110 kDa (1.5-fold) and Bcl-2-associated athanogene 3 (BAG3, 1.5-fold). Lp(a) + veh also increased expression of matrix metalloproteinase-1 (MMP-1, 1.6-fold) and antioxidant response proteins heme oxygenase-1 (HO-1, 2.6-fold) and p62 (1.7-fold). EPA treatment of Lp(a) prior to oxidation limited these protein changes as none were significantly modulated relative to control. Conclusions: EPA attenuated Lp(a)-enriched oxidation over time, which resulted in differential expression of proteins involved in HUVEC inflammatory responses. Inhibition of Lp(a) oxidation by EPA, administered as IPE, may reduce vascular dysfunction and inflammation, thereby contributing to lower CV risk in patients with elevated Lp(a) levels.