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-alpha. The anti-inflammatory effects of EPA were abrogated when the expression of peroxisome proliferator-activated receptor alpha (PPARalpha) was suppressed. EPA may potentially reduce and stabilize atherosclerotic lesions through its anti-inflammatory effects.
Matsumoto
Miwa
M
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
Sata
Masataka
M
Fukuda
Daiju
D
Tanaka
Kimie
K
Soma
Masaaki
M
Hirata
Yasunobu
Y
Nagai
Ryozo
R
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000178:diet therapy* / Q000503:physiopathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D042783:Endothelial Cells; D004730:Endothelium, Vascular; D006801:Humans; D007249:Inflammation / Q000178:diet therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001057:Apolipoproteins E; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004042:Dietary Fats, Unsaturated; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D015118:Eicosapentaenoic Acid