Chronic intermittent hypoxia induces atherosclerosis by NF-κB-dependent mechanisms

Abstract

Chronic intermittent hypoxia (CIH) causes atherosclerosis in mice fed a high cholesterol diet (HCD). The mechanisms by which CIH promotes atherosclerosis are incompletely understood. This study defined the mechanistic role of NF-κB pathway in CIH+HCD induced atherosclerosis. Wild type (WT) and mice deficient in the p50 subunit of NF-κB (p50-KO) were fed normal chow diet (ND) or HCD, and exposed to sham or CIH. Atherosclerotic lesions on the en face aortic preparation and cross-sections of aortic root were examined. In WT mice, neither CIH nor HCD exposure alone caused, but CIH+HCD caused evident atherosclerotic lesions on both preparations after 20weeks of exposure. WT mice on ND and exposed to CIH for 35.6weeks did not develop atherosclerotic lesions. P50 gene deletion diminished CIH+HCD induced NF-κB activation and abolished CIH+HCD induced atherosclerosis. P50 gene deletion inhibited vascular wall inflammation, reduced hepatic TNF-α level, attenuated the elevation in serum cholesterol level and diminished macrophage foam cell formation induced by CIH+HCD exposure. These results demonstrate that inhibition of NF-κB activation abrogates the activation of three major atherogenic mechanisms associated with an abolition of CIH+HCD induced atherosclerosis. NF-κB may be a central common pathway through which CIH+HCD exposure activates multiple atherogenic mechanisms, leading to atherosclerosis.

Propofol selectively inhibits nuclear factor-κB activity by suppressing p38 mitogen-activated protein kinase signaling in human EA.hy926 endothelial cells during intermittent hypoxia/reoxygenation

“…Emerging evidence has revealed that the activation of NF-κB in the endothelium may contribute to the pathogenic process of atherosclerosis associated with IHR (8,9). NF-κB-mediated inflammatory pathways have integrated roles in classic atherosclerosis induced by a high-cholesterol diet (9). Patients with OSA have increased NF-κB activity in circulating neutrophils and monocytes, and elevated serum levels of NF-κB-dependent gene products (10)(11)(12).…”

“…Activation of NF-κB is controlled by the inhibitor of κB (I-κB), which retains NF-κB in the cytoplasm (7). Emerging evidence has revealed that the activation of NF-κB in the endothelium may contribute to the pathogenic process of atherosclerosis associated with IHR (8,9). NF-κB-mediated inflammatory pathways have integrated roles in classic atherosclerosis induced by a high-cholesterol diet (9).…”

The associations of objectively measured sleep duration and sleep disturbances with diabetic retinopathy

“…While we did show that moderate OSA and AHI were associated with moderate DR and VTDR, we did not find any significant associations between mod OSA or AHI and DME. Chronic intermittent hypoxia is the major pathogenic feature of OSA that results in raised levels of vascular endothelial growth factor and other inflammatory cytokines that can contribute to DR progression [28][29][30]. The diagnosis and severity of OSA is based on the frequency of hypoxic episodes (apneas or hypopneas).…”

Increased internalization of complement inhibitor CD59 may contribute to endothelial inflammation in obstructive sleep apnea

“…IH increased free cholesterol content in EC plasma membrane, likely by reducing gene expression of cholesterol efflux mediators ABCA1 and ABCG1, which may underlie the increased endocytosis of CD59. Mice deficient in the p50 subunit of NFκB on a high-cholesterol diet are protected from IH-induced ABCA1 inhibition and accelerated atherosclerosis, suggesting that ABCA1 and ABCG1 inhibition in IH may be mediated by NFκB activation (39). …”