1. Selective inhibition of endothelial NF-κB signaling attenuates chronic intermittent hypoxia-induced atherosclerosis in mice.
- Author
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Song, Dongmei, Fang, Guoqiang, Mao, Sun-zhong, Ye, Xiaobing, Liu, Gang, Miller, Edmund J., Greenberg, Harly, and Liu, Shu Fang
- Subjects
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ATHEROSCLEROSIS , *NF-kappa B , *ENDOTHELIAL cells , *CELLULAR signal transduction , *HYPOXEMIA , *LABORATORY mice - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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