Safrole-2′,3′-oxide induces atherosclerotic plaque vulnerability in apolipoprotein E-knockout mice

Safrole-2′,3′-oxide (SFO) is the major electrophilic metabolite of safrole (4-allyl-1, 2-methylenedioxybenzene), a natural plant constituent found in essential oils of numerous edible herbs and spices and in food containing these herbs, such as pesto sauce, cola beverages and bologna sausages. The effects of SFO in mammalian systems, especially the cardiovascular system, are little known. Disruption of vulnerable atherosclerotic plaques in atherosclerosis, a chronic inflammatory disease, is the main cause of cardiovascular events. In this study, we investigated SFO-induced atherosclerotic plaque vulnerability (possibility of rupture) in apolipoprotein E-knockout (apoE−/−) mice. Lipid area in vessel wall reached 59.8% in high dose SFO (SFO-HD) treated group, which is only 31.2% in control group. SFO treatment changed the lesion composition to an unstable phenotype, increased the number of apoptotic cells in plaque and the endothelium in plaques was damaged after SFO treatment. Furthermore, compared with control groups, the plaque endothelium level of p75NTR was 3-fold increased and the liver level of p75NTR was 17.4-fold increased by SFO-HD. Meanwhile, the serum level of KC (a functional homolog of IL-8 and the main proinflammatory alpha chemokine in mice) in apoE−/− mice was up to 357 pg/ml in SFO-HD treated group. Thus, SFO contributes to the instability of atherosclerotic plaque in apoE−/− mice through activating p75NTR and IL-8 and cell apoptosis in plaque.

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► We demonstrate the deleterious effect of SFO in mammalian cardiovascular system.
► SFO contributes to the instability of atherosclerotic plaque.
► SFO elevated the levels of p75NTR and IL-8 and induced apoptosis in VEC.
► SFO increased serum lipid levels and increased the level of p75NTR in liver.