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.
Methods and 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.
Conclusion—
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.