P298 - EICOSAPENTAENOIC ACID (EPA) AND A GLP-1 RECEPTOR AGONIST CAUSED SYNERGISTIC CHANGES IN PROTEIN EXPRESSION AND MEDIATORS OF ENDOTHELIAL ENDOPLASMIC RETICULUM FUNCTION DURING INFLAMMATION

Background: Maintaining endoplasmic reticulum (ER) homeostasis of protein synthesis and removal of misfolded proteins is essential to cell function. This process is aided by protein OS-9 (OS-9) which regulates the ER-associated degradation system. EPA administered as icosapent ethyl reduced cardiovascular (CV) events in high-risk patients (REDUCE-IT). GLP-1 receptor agonists (GLP-1RA) also have CV benefits. We measured the separate versus combined effects of the GLP-1RA liraglutide (lira) and EPA on expression of OS-9 and related proteins in endothelial cells following angiotensin II (Ang II) challenge.

METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were challenged with Ang II (100 nM) for 2 h, then treated with lira (50 nM) and/or EPA (40 µM) for 24 h. Global proteomic analysis performed by mass spectroscopy measured relative protein levels simultaneously. Changes in expression between treatment groups >1-fold with p< 0.05 were considered significant. Gene set enrichment analysis (GSEA) was performed on all detected proteins. The EPA+lira combination significantly changed the expression of >40 unique proteins vs Ang II alone that maintain endothelial function. GSEA revealed the combination significantly affected 16 proteins within the “endoplasmic reticulum membrane” pathway (GO: 0005789). Separately, EPA and lira significantly modulated ten and one of these proteins, respectively. The combination treatment caused a synergistic increase in expression of OS-9 (1.1-fold, p=0.0005). Other changes exclusive to the combination include decreases in vitamin K epoxide reductase complex subunit 1 (1.2-fold, p=0.0004), a coagulation promoter, and the pro-inflammatory mediator toll-like receptor 9 (1.1-fold, p=0.0005). The combination increased NQO1 expression (50%, p< 0.05). These effects were not observed with EPA and lira separately.

Conclusion: EPA and lira caused synergistic effects on cellular pathways related to endoplasmic reticulum function and cytoprotection in endothelial cells during inflammation. These actions of a GLP-1RA on protein expression when combined with EPA may enhance CV protection.