Endogenously Decreasing Tissue n-6/n-3 Fatty Acid Ratio Reduces Atherosclerotic Lesions in Apolipoprotein E –Deficient Mice by Inhibiting Systemic and Vascular Inflammation

Abstract

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.