Arsenic trioxide ameliorates atherosclerosis by inhibiting CD36-induced
endocytosis and TLR4/NF-κB-induced inflammation in macrophage and
ApoE-/- mice
Abstract
Background and Purpose Inflammation and lipid accumulation are key
events in atherosclerosis progression. Arsenic trioxide (ATO) has been
reported to prevent vascular restenosis by promoting smooth muscle
apoptosis and rapid initialization. However, its specific role and
mechanism underlying its role in atherosclerosis remain unknown. Herein,
we evaluated whether ATO suppresses atherosclerotic plaque development
and instability. Experimental Approach ApoE-/- mice were fed a high-fat
diet for 3 months and treated with ATO every alternate day for 30 days.
The carotid artery and serum samples were collected to determine
atherosclerotic lesion size, histological features, and related protein
and lipid profiles. In vitro, RAW264.7 or THP-1 cells were stimulated
using oxidized low-density lipoprotein (ox-LDL) or LPS to explore the
anti-inflammatory and anti-pyroptosis effects of ATO. Key Results ATO
reduced atherosclerotic lesion formation and plasma lipid levels in
ApoE-/- mice. Additionally, it reduced the levels of various
pro-inflammatory factors, including IL-6 and TNFα, in the serum and
aortic plaques, but increased the IL-10 level. Mechanistically, ATO
promotes the CD36-mediated internalization of ox-LDL, which may explain
the reduction in blood lipid levels. Further, ATO reduced TLR4
expression in plaques and macrophages and inhibited LPS-induced p65
nuclear translocation and IκB-α degradation. Conclusion and Implications
ATO has the potential atheroprotective effects, especially in
macrophages. The mechanisms include inhibition of CD36-mediated foam
cell formation, inflammatory responses, and pyroptosis via the
suppression of TLR4/NF-κB and NLRP3 activation. Our findings provide
evidence for the potential atheroprotective value of ATO.