Dongmei Song1, Guoqiang Fang2, Sun-Zhong Mao2, Xiaobing Ye2, Gang Liu2, Edmund J Miller2, Harly Greenberg2, Shu Fang Liu3. 1. The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Center for Pulmonary, Critical Care and Sleep Medicine, The Feinstein Institute for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA. Electronic address: dongmeisong2016@126.com. 2. Center for Pulmonary, Critical Care and Sleep Medicine, The Feinstein Institute for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA. 3. The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Center for Pulmonary, Critical Care and Sleep Medicine, The Feinstein Institute for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA. Electronic address: SLiu@northwell.edu.
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-ECI-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-ECI-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-ECI-κBmt mice significantly inhibited CIH-induced NF-κB activity, and suppressed E-selectin and VCAM-1 expressions, confirming endothelial NF-κB inhibition in ApoE-ECI-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-ECI-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.
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-ECI-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-ECI-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-ECI-κBmt mice significantly inhibited CIH-induced NF-κB activity, and suppressed E-selectin and VCAM-1 expressions, confirming endothelial NF-κB inhibition in ApoE-ECI-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-ECI-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.