Omega-3 Fatty Acids Inhibit Endoplasmic Reticulum (ER) Stress in Human Coronary Artery Endothelial Cells

Abstract

The biological effects of fatty acids differ by their structure. Saturated fatty acids and trans-fatty acids are recognized as promoters of coronary artery disease (CAD), while monounsaturated and omega-3 fatty acids may have salutary effects. Since cellular stress is recognized as a fundamental driver of CAD, the effect of these fatty acids on endoplasmic reticulum (ER) stress in human coronary artery endothelial cells (HCAECs) was measured using the ER stress-responsive alkaline phosphatase (ES-TRAP) assay. Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and eicosapentaenoic acid ethyl ester (EPA-EE) suppressed ER stress induced with pharmacologic (tunicamycin) and physiologic (high-dextrose concentration) ER stress inducers. In tunicamycin-treated cells, DHA reduced the expression of unfolded protein response (UPR) markers such as phosphorylation of inositol requiring enzyme 1α (IRE1α) and protein kinase R-like endoplasmic reticulum kinase (PERK) and increased activating transcription factor 6 (ATF6) and glucose regulated protein 78 (GRP78) expression. Similarly, treatment with both oleic acid and arachidonic acid, but not elaidic acid (a trans-fatty acid), suppressed both tunicamycin and high-dextrose-induced ER stress while treatment with saturated fatty acids (C14 : 0, C16 : 0, and C18 : 0) enhanced both tunicamycin and high-dextrose-induced ER stress. The latter fatty acids at higher concentrations caused cytotoxicity. These results indicate that omega-3 fatty acids as well as select unsaturated fatty acids and arachidonic acid suppress ER stress in HCAEC.