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

Abstract 

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.

Abbreviations: n-3 PUFAs, n-3 polyunsaturated fatty acids, AA, arachidonic acid, EPA, eicosapentaenoic acid, DPA, docosapentaenoic acid, DHA, docosahexaenoic acid, HUVECs, human umbilical vein endothelial cells, MMP, matrix metalloproteinase, siRNA, small interference RNA, PPAR, peroxisome proliferator-activated receptor, VCAM, vascular cellular adhesion molecule, ICAM, intercellular adhesion molecule

Keywords: Inflammation, Pathology, Atherosclerosis, Leukocytes, Prostaglandins