Objective— Expression of human apolipoprotein (h-apo) A-IV in apoE-deficient (apoE ₀ ) mice (h-apoA-IV/E ₀ ) reduces susceptibility to atherosclerosis. Chronic infection mimicked by exposure to lipopolysaccharide (LPS) increases the size of atherosclerosis lesions in apoE ₀ mice. Thus, we used h-apoA-IV/E ₀ mice to determine whether h-apoA-IV plays a protective role after LPS administration. Methods and Results— We injected apoE ₀ , h-apoA-IV/E ₀ , and C57Bl/6 (wild-type) mice intraperitoneally with either LPS or phosphate-buffered saline (PBS) every week for 10 weeks. Atherosclerotic lesions were significantly smaller in h-apoA-IV/E ₀ mice treated with LPS than in their apoE ₀ counterparts. The titers of IgG2a and IgG2b autoantibodies to oxidized low-density lipoprotein (LDL) were higher in the LPS-group of h-apoA-IV/E ₀ mice than in apoE ₀ mice, suggesting that the Th1 response is stronger in the presence of h-apoA-IV. Lymphocytes from the blood, liver, spleen, and thymus of h-apoA-IV/E ₀ mice treated with LPS produced less IL-4, INF-γ, and TNF-α proinflammatory cytokines than their apoE ₀ counterparts. Furthermore, we demonstrated that recombinant h-apoA-IV blocks the LPS-induced stimulation of monocytes. Conclusions— The expression of h-apoA-IV in apoE ₀ mice reduces the susceptibility to atherogenesis and decreases the secretion of proinflammatory cytokines after LPS administration.

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