The atheroprotective role of lipoxin A prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway.

Background And Aims: We examined whether the inflammation resolution mediator lipoxin A (LXA) inhibits foam cell formation and oxidized low-density lipoprotein (oxLDL)-induced apoptotic signaling in macrophages and the role of circulating/local LXA biosynthesis in atherogenesis.

Methods: LXA levels were measured by enzyme-linked immunosorbent assay. Dil-oxLDL and Dil-acLDL binding to and uptake by macrophages were evaluated by flow cytometry. Apoptosis was evaluated by TUNEL and Annexin V/PI assays.

Results: Circulating LXA levels in patients with coronary artery disease were much higher than those in respective controls. Local LXA levels were much lower in rabbit atherosclerotic vessel walls. Interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) were elevated in atherosclerotic vessels. After the inflammatory stimulus (IFN-γ, TNF-α, and C-reactive protein), LXA synthesis decreased significantly in foam cells. LXA dose-dependently suppressed the expression of the cholesterol uptake genes CD36 and SR-A in macrophages, which was blocked by the LXA receptor antagonist BOC-2. LXA also inhibited oxLDL-induced CD36 upregulation, Dil-oxLDL uptake, and foam cell formation. Furthermore, LXA inhibited the oxLDL-activated c-Jun N-terminal kinase pathway and reduced oxLDL-induced macrophage apoptosis by inhibiting caspase-3 activation and restoring the mitochondrial membrane potential.

Conclusions: We found that LXA inhibited foam cell formation, oxLDL-induced inflammation, and apoptotic signaling in macrophages. Insufficient levels of the anti-inflammatory pro-resolution molecule LXA were found in rabbit atherosclerotic arteries, which might contribute to preventing inflammation resolution during atherogenesis.