Selective inhibition of endothelial NF-κB signaling attenuates chronic intermittent hypoxia-induced atherosclerosis in mice.

Background and Aims: Chronic intermittent hypoxia (CIH) exposure causes atherosclerosis, although the underlying mechanisms are poorly understood. This study defines the role of endothelial intrinsic NF-κB signaling in the atherogenic response to CIH.
Methods: We created ApoE-EC ^I-κBmt mice that are deficient in the apolipoprotein E gene (ApoE ^-/- ) and overexpress an I-κBα mutant (I-κBmt) selectively in endothelial cells. ApoE ^-/- and ApoE-EC ^I-κBmt mice were fed a normal chow diet (NCD) or high cholesterol diet (HCD) and exposed to sham or CIH, and atherosclerotic lesions were quantified.
Results: CIH exposure activated NF-κB in aortas, and induced the expression of endothelial-specific and NF-κB-dependent genes, E-selectin and vascular cell adhesion molecule (VCAM)-1, in the aortas and hearts. Endothelial I-κBmt overexpression in ApoE-EC ^I-κBmt mice significantly inhibited CIH-induced NF-κB activity, and suppressed E-selectin and VCAM-1 expressions, confirming endothelial NF-κB inhibition in ApoE-EC ^I-κBmt mice. ApoE ^-/- mice, on NCD, developed mild atherosclerotic lesions spontaneously, and developed advanced and larger areas of atherosclerotic plaques when exposed to CIH. ApoE ^-/- mice also developed advanced atherosclerotic lesions when fed an HCD alone. The HCD-induced atherosclerotic plaques became more advanced, and plaque area was doubled in mice exposed to HCD + CIH. Endothelial I-κBmt overexpression in ApoE-EC ^I-κBmt mice attenuated spontaneously developed atherosclerotic lesions, abrogated CIH-induced atherosclerosis and mitigated CIH-mediated facilitation of HCD-induced atherosclerosis.
Conclusions: These results suggest that endothelial intrinsic NF-kB signaling may play a pivotal role in CIH-induced atherosclerosis.
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