Emerging Pathways of Action of EPA. Eicosapentaenoic acid (EPA) promotes broad anti-inflammatory effects in T cells and endothelial cells through directed changes in gene and protein expression that may limit progression of atherosclerosis beyond triglyceride lowering. When activated by binding to antigens, T cells release inflammatory signals that promote atherosclerosis in a subset-dependent manner. Following activation through toll-like receptors, naïve CD4⁺ T cells polarize to distinct cell populations with release of various cytokines and signaling molecules such as CD69, CD25, and interleukin 2 receptor subunit alpha (IL2RA). Activated cells express CD40L that assist the function of B cells and other immune cells. In parallel fashion, activated endothelial cells express adhesion molecules and release proinflammatory factors, along with increased vascular permeability and reduced nitric oxide (NO) release. Reilly et al6 reported that EPA treatment induces anti-inflammatory changes in T cell transcriptomes that complement proteomic findings in vascular endothelial cells.6 In both T cells and endothelial cells, EPA increased expression and release of cytoprotective proteins such as HO-1/HMOX1, NAD(P)H dehydrogenase [quinone] 1 (NQO1/NQO1), and antioxidant response element (ARE) transcription products. Separately, EPA reduced transcription in nonactivated CD4⁺ T cells of CD69, IL2RA, major histocompatibility complex, class II, DR alpha (HLA-DRA), GATA binding protein 3 (GATA3), purine-rich box1 (PU.1) while increasing levels of carnitine palmitoyltransferase 1A (CPT1A) and REV-ERB, all of which indicate a reduction in T cell activation of polarization toward proinflammatory subsets and increased polarization to anti-inflammatory subsets including Treg. Under conditions of inflammation, EPA improves endothelial NO synthase (eNOS) coupling and bioavailability with increased expression of dimethylarginine dimethylaminohydrolase 1 (DDAH-1) and the detoxification protein peroxiredoxin-2 (PRDX2), while reducing expression of vascular cell adhesion protein 1 (VCAM-1), cytokines, and vascular permeability. Other actions of EPA include antithrombotic effects, cell-membrane stabilizing properties, and reduction of plaque progression.