Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice

Accumulating evidence demonstrates that dietary intake of n-3 polyunsaturated fatty acids (PUFAs) is associated with reduced incidence of cardiovascular events. However, the molecular mechanisms by which n-3 PUFAs prevent atherosclerosis are not fully understood. Here, we examined the effect of eicosapentaenoic acid (EPA), a major n-3 PUFA, on the pathogenesis of atherosclerosis in ApoE-deficient mice. Five-week-old ApoE-deficient male mice were fed on western-type diet supplemented with 5% (w/w) EPA (EPA group, n = 7) or not (control group, n = 5) for 13 weeks. An analysis of the fatty acid composition of liver homogenates revealed a marked increase of the n-3 PUFA content in the EPA group (n-3/n-6 ratio: 0.20 ± 0.01 vs. 2.5 ± 0.2, p < 0.01). En face Sudan IV staining of the aorta and oil red O-staining of the aortic sinus revealed that EPA significantly suppressed the development of atherosclerotic lesions. We also observed anti-atherosclerotic effects of EPA in LDL-receptor-deficient mice. The lesions of the EPA group contained more collagen (19.6 ± 2.4% vs. 32.9 ± 3.9%, p < 0.05) and smooth muscle cells (1.3 ± 0.2% vs. 3.6 ± 0.8%, p < 0.05) and less macrophages (32.7 ± 4.1% vs. 14.7 ± 2.0%, p < 0.05). Pretreatment with EPA attenuated the up-regulation of VCAM-1, ICAM-1 and MCP-1 in HUVECs as well as the expression of MMP-2 and MMP-9 in macrophage-like cells induced by TNF-α. The anti-inflammatory effects of EPA were abrogated when the expression of peroxisome proliferator-activated receptor alpha (PPARα) was suppressed. EPA may potentially reduce and stabilize atherosclerotic lesions through its anti-inflammatory effects.