Lipoxin A₄ and its analog attenuate high fat diet-induced atherosclerosis via Keap1/Nrf2 pathway

Excessive oxidative stress and decreased antioxidant capacity of macrophages are initial factors which cause macrophages to transform to foam cells, which represents a key event in the progression of atherosclerosis (AS). BML-111, the analog of lipoxin A₄ (LXA₄) strongly attenuated high fat (HF) diet-induced atherosclerosis by activating NF-E2 related factor 2 (Nrf2). However, the effect was not through a specific LXA₄ receptor (formyl peptide receptor 2, FPR2). BML-111 also strongly inhibited HF diet-induced promotion of MDA level, increased HDL level and decreased IL-1, MCP-1, IL-6, VCAM, ICAM and TNF-α level in aorta. In the in vitro experiments, LXA₄ inhibited THP-1 cells to transform to foam cells via Nrf2 pathway. Our findings demonstrated that LXA₄ and its analog prevented AS induced by HF diet in SD rats, under which the possible mechanism is through Keap1/Nrf2 pathway.