Fish oil, containing omega-3 fatty acids, attenuates atherosclerosis. We hypothesized that omega-3 fatty acid–enriched oils are atheroprotective through alteration of monocyte subsets and their trafficking into atherosclerotic lesions.

Low–density lipoprotein receptor knockout and apolipoprotein E^−/− mice were fed diets containing 10% (calories) palm oil and 0.2% cholesterol, supplemented with an additional 10% palm oil, echium oil (containing 18:4 n-3), or fish oil. Compared with palm oil–fed low–density lipoprotein receptor knockout mice, echium oil and fish oil significantly reduced plasma cholesterol, splenic Ly6C^hi monocytosis by ≈50%, atherosclerosis by 40% to 70%, monocyte trafficking into the aortic root by ≈50%, and atherosclerotic lesion macrophage content by 30% to 44%. In contrast, atherosclerosis and monocyte trafficking into the artery wall was not altered by omega-3 fatty acids in apolipoprotein E^−/− mice; however, Ly6C^hi splenic monocytes positively correlated with aortic root intimal area across all diet groups. In apolipoprotein E^−/− mice, fish oil reduced the percentage of blood Ly6C^hi monocytes, despite an average 2-fold higher plasma cholesterol relative to palm oil.

The presence of splenic Ly6C^hi monocytes parallels the appearance of atherosclerotic disease in both low–density lipoprotein receptor knockout and apolipoprotein E^−/− mice. Furthermore, omega-3 fatty acids favorably alter monocyte subsets independently from effects on plasma cholesterol and reduce monocyte recruitment into atherosclerotic lesions.