Naringin (NAR) from grapefruit has exhibited potential protective effects against
atherosclerosis development. However, specific mechanisms responsible for such effects are poorly understood. Thus, we aimed to investigate the antiatherogenic effects of NAR in different mouse models of
hypercholesterolemia and decipher its molecular targets in the aorta using transcriptomic approach. Two mouse models of
hypercholesterolemia, wild-type mice fed a high-fat/high-
cholesterol diet and
apolipoprotein E-deficient mice fed a semisynthetic diet, were studied. Mice were fed a respective control diets supplemented or not for 18 weeks with 0.02% of NAR, that is, nutritional supplementation. NAR supplementation reduced plaque progression only in wild-type mice fed the high-fat/high-
cholesterol diet (-41%). Consistent with this protective effect, NAR reduced plasma non-
high-density lipoprotein cholesterol concentrations as well as
biomarkers of endothelial dysfunction. Microarray studies performed on aortas demonstrated differentially expressed genes encoding
proteins involved in cell adhesion, actin cytoskeleton organization and cell division. Thus, the changes in gene expression induced by NAR could suggest a limited
atherosclerosis progression by preventing immune cell adhesion and infiltration in the intima of vascular wall, as well as smooth muscle cell proliferation. Furthermore, this hypothesis was strengthened by in vitro experiments, which showed the ability of
naringenin to reduce monocyte adhesion to endothelial cells and smooth muscle cell proliferation. In conclusion, this study revealed the antiatherogenic effect of NAR supplemented at a nutritionally achievable dose, specifically toward diet-induced
atherosclerosis, and depicted its multitarget mode of action at the vascular level.