(P005) COMBINATION OF EICOSAPENTAENOIC ACID (EPA) AND HIGH INTENSITY STATIN MODULATED THE EXPRESSION OF DETOXIFICATION PROTEINS IN ENDOTHELIAL CELLS DURING INFLAMMATION IN VITRO

Background: Cellular detoxification enzymes including peroxiredoxins (PRDX) inactivate reactive oxygen species (ROS) during endothelial dysfunction. These atheroprotective proteins also include heme oxygenase-1 (HO-1). EPA administered as icosapent ethyl (IPE) reduced cardiovascular (CV) events in high-risk, statin-treated patients (REDUCE-IT), but the mechanism is not fully understood. We measured the effects of EPA and rosuvastatin (rosuva) on expression of proteins involved in detoxification following stimulation with angiotensin II (Ang II).

METHODS AND RESULTS: Human umbilical vein ECs (HUVECs) were challenged with Ang II (100 nM) for 2 h, then treated with rosuva (10 µM) and/or EPA (40 µM) for 24 h. Global proteomic analysis performed by mass spectroscopy (LC/MS) measured the relative expression levels simultaneously. Significant (p < 0.05) changes in expression between treatment groups >1-fold were analyzed and included in gene set enrichment analyses (GSEA). Levels of HO-1 were measured using immunochemical approaches. Compared to Ang II alone, rosuva alone did not affect expression of proteins related to ROS detoxification. But rosuva combined with EPA significantly modulated 9 proteins within the “cellular response to reactive oxygen species” pathway (GO: 0034614, adjusted-p = 0.0142) relative to Ang II alone. This included a 1.1-fold increase in expression of PRDX5, heat shock protein 70, and glutathione reductase. EPA alone also modulated thioredoxin reductase 1 (1.2-fold increase, p = 0.019). Addition of EPA to rosuva increased HO-1 expression by 173% (p < 0.01) while rosuva alone had no effect.

Conclusion: In endothelial cells, EPA enhanced expression of ROS detoxification proteins and a related pathway in combination with rosuvastatin. These proteins included peroxiredoxin isoforms, glutathione reductase, and HO-1. These benefits of EPA with a statin on protein expression during inflammation may contribute to reduced risk in CV outcome trials.