Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-κB p50.

Current animal models of chronic intermittent hypoxia (CIH)-induced atherosclerosis have limitations. Mechanisms of CIH-induced atherosclerosis are poorly understood. This study tested new mouse models of CIH-induced atherosclerosis and defined the role of NF-κB p50 in CIH-induced atherosclerosis. Mice deficient in apolipoprotein E (ApoE-KO) or in both ApoE and p50 genes (ApoE-p50-DKO) were exposed to sham or CIH. Atherosclerotic lesions on aortic preparations were analyzed. CIH exposure caused atherosclerosis in ApoE-KO mice fed a normal chow diet and with no preexisting atherosclerotic condition in an exposure time-dependent manner. CIH caused more pronounced atherosclerotic lesions in ApoE-p50-DKO mice on a normal chow diet without preexisting atherosclerosis. ApoE-KO and ApoE-p50-DKO mice exposed to CIH for 30 and 9 weeks, respectively, displayed similar areas of atherosclerotic lesions on cross sections of aortic root. P50 gene deletion in ApoE-p50-DKO mice significantly augmented CIH-induced serum levels of tumor necrosis factor-α and IL-6, aortic tumor necrosis factor-α, and inducible nitric oxide synthase expression and aortic infiltration of Mac3-positive macrophages. CIH caused a greater elevation in serum cholesterol level in ApoE-p50-DKO than in ApoE-KO mice. CIH down-regulated hepatic low-density lipoprotein receptor and HMG-CoA reductase expression in ApoE-p50-DKO but not in ApoE-KO mice. We found two new mouse models that are useful for studying mechanisms and pathways of CIH-induced atherosclerosis. We showed that NF-κB p50 protects against CIH-induced atherosclerosis by inhibiting vascular inflammation and hypercholesterolemia.