The role of omega-3 fatty acids in determining monocyte and macrophage phenotypes in experimental atherosclerosis.

摘要

Dietary omega-3 polyunsaturated fatty acids, primarily eicosapentaenoate (EPA) and docosahexaenoate (DHA), attenuate chronic diseases such as atherosclerosis. However, fatty fish, the richest dietary source of omega-3 fatty acids, is consumed in low quantities in the U.S. Therefore, we sought to determine whether a botanical oil, echium oil from Echium plantagineum that is enriched in stearidonic acid (SDA; 18:4 n-3), will alter monocyte and macrophage phenotypes in murine models of atherosclerosis. This dissertation addresses the considerable gaps in knowledge regarding the atheroprotective and anti-inflammatory potential of echium oil supplementation. Furthermore, this work helped elucidate the role of omega-3 fatty acids in CVD prevention, and clarify the immunomodulatory properties of omega-3 fatty acids.;We hypothesized that omega-3 fatty acid-enriched oils are atheroprotective as a result of alterations of monocyte subsets and monocyte trafficking into atherosclerotic lesions. We measured blood and splenic monocyte populations via flow cytometry in both LDLr-/- and apoE-/- mice. We determined that splenic Ly6Chi monocytes parallel atherosclerotic disease in both models. Furthermore, omega-3 fatty acids favorably alter monocyte subsets independently from effects on plasma cholesterol, and reduce monocyte recruitment into atherosclerotic lesions.;We also explored the likelihood that omega-3 fatty acids promote macrophage phenotype shifting from a more inflammatory (M1) to a less inflammatory (M2) alternative phenotype. Using flow cytometry and gene expression analysis, we determined that echium and fish oil feeding increased the M2 phenotype of murine macrophages.;In summary, botanical omega-3 fatty acids, which are efficiently converted in vivo to the bioactive molecule EPA have implications for reducing the incidence and severity of many human diseases, including atherosclerosis. The findings in this dissertation suggest that echium oil may be a satisfactory replacement for fish oil for the amelioration of such diseases. We provide insight into the mechanisms by which omega-3 fatty acids fundamentally alter monocyte and macrophage populations in the pathogenesis of atherosclerosis. Overall, these findings have implications in broadening our understanding of the complex interactions between the inflammatory, pathological processes of cardiovascular disease, and dietary fatty acid consumption.