Endogenously decreasing tissue n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apolipoprotein E-deficient mice by inhibiting systemic and vascular inflammation.
OBJECTIVE
To use the fat-1 transgenic mouse model to determine the role of tissue n-6/n-3 fatty acid ratio in atherosclerotic plaque formation. Although it has been suggested that a low ratio of n-6/n-3 polyunsaturated fatty acids (PUFAs) is more desirable in reducing the risk of atherosclerotic cardiovascular disease, the role of tissue n-6/n-3 fatty acid ratio in atherosclerosis has not been sufficiently tested in a well-controlled experimental system. The fat-1 transgenic mouse model, expressing an n-3 fatty acid desaturase, is capable of producing n-3 PUFAs from n-6 PUFAs and thereby has a ratio of n-6/n-3 fatty acids close to 1:1 in tissues and organs.


RESULTS
To generate apolipoprotein E-deficient plus fat-1 transgenic mice (apoE(-/-)/fat-1), we crossed heterozygous fat-1 mice with apoE(-/-) mice. After 14 weeks of a Western-type diet rich in n-6 PUFAs, the apoE(-/-)/fat-1 mice showed a lower ratio of n-6/n-3 fatty acids than the apoE(-/-) mice in all organs and tissues tested. The aortic lesion area in apoE(-/-)/fat-1 mice was significantly reduced when compared with that of apoE(-/-) littermates (7.14±0.54% versus 13.49±1.61%). There were no differences in plasma cholesterol or high- and low-density lipoprotein levels between the 2 groups, except for a higher triglyceride level in the apoE(-/-)/fat-1 mice. A significant reduction of interleukin 6 and prostaglandin E(2) in both plasma and aorta culture medium was observed in apoE(-/-)/fat-1 mice. RT-PCR analysis also indicated that the expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, interleukin 6, and cyclooxygenase-2 was lower in the aortas and the circulating monocytes from apoE(-/-)/fat-1 mice. In addition, the expression of nuclear factor κB/p65 in the aorta and the recruitment of macrophages into atherosclerotic plaques were reduced in apoE(-/-)/fat-1 mice, compared with apoE(-/-) mice.


CONCLUSIONS
To our knowledge, this is the first study to provide direct evidence for the role of tissue n-6/n-3 ratio in atherosclerosis using the fat-1 transgenic mouse model. Our findings demonstrate that a decreased n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apoE(-/-) mice. This protective effect may be attributed to the antiinflammatory properties of n-3 fatty acids, rather than their lipid-lowering effect.
Wan
Jian-Bo
JB
Laboratory for Lipid Medicine and Technology, the Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Huang
Li-Li
LL
Rong
Rong
R
Tan
Rui
R
Wang
Jingdong
J
Kang
Jing X
JX
D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D051546:Cyclooxygenase 2 / Q000235:genetics; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D004435:Eating; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000097:blood / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008077:Lipoproteins, LDL / Q000097:blood; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013997:Time Factors; D046509:Tissue Culture Techniques; D051996:Transcription Factor RelA / Q000378:metabolism
D001057:Apolipoproteins E; D029742:Caenorhabditis elegans Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D018836:Inflammation Mediators; D015850:Interleukin-6; D008077:Lipoproteins, LDL; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C466741:fat-1 protein, C elegans; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol; D044943:Fatty Acid Desaturases; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone