Isocaloric Walnut Inclusion in a Palm-Based High-Fat and High-Cholesterol Diet Stabilizes Advanced Atheroma Plaque in ApoE-Deficient Mice

Abstract

Abstract Objectives The presence of lipid-rich, unstable atheroma plaques in the vascular tree is the harbinger of cardiovascular events. There is a low prevalence of unstable atheroma plaques in Mediterranean countries. This might explain in part the lower rates of cardiovascular disease in Southern Europe compared to Northern Europe and US. Consumption of certain foods paradigmatic of the Mediterranean Diet delays atherosclerosis progression. In a mouse model of accelerated atherosclerosis, we investigated whether the inclusion of walnuts within an atherogenic diet stabilizes advanced atheroma plaque. Methods Apolipoprotein E-deficient mice (male, 10-week old) were randomized to receive either regular chow (9.6% of energy as fat, n = 14); a palm oil-based high-fat diet (43% of energy as fat, n = 15); or an isocaloric high-fat diet in which palm oil was partially replaced by walnuts in a dose equivalent to 30 g/d in humans (n = 14). All diets contained 0.2% cholesterol. After 15 weeks of intervention, we evaluated changes in aortic atherosclerotic lesions (size and composition) and markers for inflammation, oxidative stress, necrosis and autophagy. Results There were no among-group differences in atherosclerotic size and extension, or oxidative stress. Compared to control diet, palm oil-diet induced plaque instability (higher lipid and necrosis, and lower collagen-to-lipid ratio). Walnut inclusion attenuated these features and decreased macrophage infiltration. Palm oil-based diet increased expression of chemokines, cytokines, inflammasome, and M1-macrophage marker compared to control diet. Such response was not observed in walnut group. Findings for walnut group could be explained by the differential aortic activation of NF-kB (down-regulated) and Nrf2 and autophagy (up-regulated). Conclusions Isocaloric inclusion of walnuts within an unhealthy high-fat diet stabilizes advanced atheroma plaque. This contributes novel mechanistic evidence for the cardiovascular benefits of sustained walnut consumption. Funding Sources Instituto de Salud Carlos III, Spain; Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional, Spain. California Walnut Commission.