Pretreatment with N-6 PUFA Protects Against Subsequent High Fat Diet Induced Atherosclerosis--potential Role of Oxidative Stress-induced Antioxidant Defense

Objectives: Recent evidence suggests that oxidative stress can promote antioxidant defense and thus be athero-protective. n-6 polyunsaturated fatty acids (n-6 PUFA) are more prone to oxidation, compared to monounsaturated fatty acids (MUFA) and yet have proven anti-atherosclerotic effects. In this study, we tested whether early exposure to a diet rich in n-6 PUFA, compared to a MUFA rich diet would reduce lesion burden, even with subsequent exposure to a high fat, high cholesterol diet (HF). Further, we tested to determine whether oxidative mechanisms are involved in such protection.

Methods And Results: Twenty four, 4 week old, male, LDL receptor knockout (LDL-R(-/-)) mice were divided into two groups and fed either a n-6 PUFA rich or a MUFA rich diet for a period of 12 weeks. At this point, 4 mice from each group were euthanized and the remaining 8 mice from each group were fed a HF diet for four weeks. Atherosclerotic lesions, plasma lipids, autoantibodies to lipid peroxide modified proteins, isoprostanes and aortic catalase levels were measured. The n-6 PUFA diet reduced aortic lesions and plasma lipids compared to the MUFA diet and this reduction in lesions continued even after the mice were switched over to the HF diet, despite the fact that the plasma lipids were similar in both groups after the HF diet. n-6 PUFA fed mice had highest plasma isoprostane levels, indicating oxidative stress, but also had higher levels of aortic catalase. On the other hand, MUFA fed mice had comparatively lower levels of isoprostanes and their aortic catalase levels remained low. Finally, aortic lesions were negatively correlated with isoprostanes and catalase.

Conclusion: An initial exposure to a n-6 PUFA rich diet compared to a MUFA rich diet reduces atherosclerotic lesions and this protection probably involves oxidative stress induced by PUFA.