Chronic low-grade inflammation is a major factor in all stages of cardiovascular disease (CVD), from initiation to progression [1]. Pharmacologic treatments that selectively target pro-inflammatory pathways without altering plasma lipoprotein concentrations have been shown to significantly reduce CVD, confirming the critical involvement of inflammation in atherosclerosis [2]. The very long-chain ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) exhibit anti-inflammatory properties, such as reducing the expression of cytokines, chemokines, and cell adhesion proteins, as well as modulating the functions of innate and adaptive immune cells [3]. Monocytes and macrophages are part of the innate immune system, responsible for the development and progression of atherosclerosis. They are among the key cellular targets of the anti-inflammatory effects of ω-3 PUFAs. EPA and DHA also generate bioactive compounds called specialized pro-resolving lipid mediators (SPMs) that activate the resolution phase of inflammation by shaping macrophages toward a pro-resolving and anti-inflammatory phenotype with enhanced capacity of efferocytosis and tissue remodeling [4].

Despite the extensive experimental evidence of the anti-inflammatory effects of very long chain ω-3 PUFAs, clinical supplementation trials have elicited conflicting results, with some, but not all, studies showing a lower risk of CVD [5]. Notably, the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) [6] and JELIS (Japan EPA Lipid Intervention Study) [7] trials, both of which involved administering high-dose pure EPA supplements, demonstrated a significant reduction in the incidence of CVD events. The discrepancy observed between these trials of pure EPA and the mixed ω-3 PUFA supplementation trials emphasizes the significance of understanding the distinct effects of EPA and DHA, especially in managing inflammation. The different biophysical characteristics of EPA and DHA may result in unique effects on inflammatory signals [8] and cell bioenergetics, in addition to producing different SPMs and prostaglandins/leukotrienes. Furthermore, the sex-dependent impacts of ω-3 PUFAs have been understudied despite an increasing interest [9,10].

Thus, our aim was to evaluate, through transcriptomic profiling, the effects of high-dose (3 g/day) pure EPA and DHA supplementation on monocytes isolated from men and postmenopausal women with chronic low-grade inflammation. We also aimed to determine the potential association between alterations in monocyte gene expression and plasma profiles of ω-3 PUFA-derived SPMs.