Intermittent hypoxia and hypercapnia induces inhibitor of nuclear factor-κB kinase subunit β-dependent atherosclerosis in pulmonary arteries

Abstract

Clinical studies have shown that obstructive sleep apnea (OSA) increases atherosclerosis risk. The inflammation, especially mediated by the macrophages via nuclear factor-κB (NF-κB), has been speculated to contribute to atherogenicity in OSA patients. Inhibitor of NF-κB kinase-β (IKKβ) is an essential element of the NF-κB pathway and is linked to atherosclerosis. We previously reported that atherosclerosis was accelerated in pulmonary artery (PA) but not in aorta when low-density lipoprotein receptor knockout ( Ldlr−/−) mice were exposed to intermittent hypoxia/hypercapnia (IHH), a surrogate for recurrent upper-airway obstruction. Therefore, we hypothesized that IKKβ-dependent NF-κB activation in monocytes and macrophages plays a role in IHH-induced PA atherosclerosis. To test this hypothesis, myeloid restricted IKKβ deletion ( IkkβΔMye) or control ( IkkβF/F) mice were crossed with Ldlr−/− mice to generate double-knockout mice. Then, the mice were exposed to IHH or room air (Air) on high-fat diet for 8 or 16 wk. Lesions of PA and aorta were examined in IkkβΔMye; Ldlr−/− and IkkβF/F; Ldlr−/− male mice under IHH vs. Air. The results revealed that IKKβ deletion abolished IHH-induced PA atherosclerosis after 8-wk exposure but not after 16-wk exposure (8 wk: IkkβF/F; Ldlr−/−, IHH 13.5 ± 1.4 vs. Air 5.7 ± 0.7%, P < 0.01; IkkβΔMye; Ldlr−/−, IHH 7.4 ± 1.9% vs. Air 4.6 ± 1.3%, P = 0.24). Both IKKβ deletion and IHH had no effects on atherosclerosis in the aorta. Our findings demonstrate that IKKβ-dependent NF-κB activity in myeloid-lineage cells plays a critical role in IHH-induced PA atherosclerosis at the early stage.

Influence of Intermittent Hypoxia/Hypercapnia on Atherosclerosis, Gut Microbiome, and Metabolome

“…We have shown that atherosclerosis can be promoted by IHC in the PA trunk and its proximal branches of both ApoE −/− and Ldlr −/− mice (Douglas et al, 2013;Xue et al, 2017;Imamura et al, 2019), demonstrating that the effect of IHC on the PA is not genetic background-dependent. The current IH and IC data corroborate the notion that PA atherosclerosis is promoted by these blood gas changes as well.…”

Effects of Normoxic Recovery on Intima-Media Thickness of Aorta and Pulmonary Artery Following Intermittent Hypoxia in Mice

“…Medial thickness of the pulmonary artery (PA) is increased by hypoxia in mice (Hales et al, 1983;Wanstall et al, 2002;Matsui et al, 2004;Ambalavanan et al, 2005;Yu et al, 2008;Mizuno et al, 2011) and in rats (Meyrick and Reid, 1980;Hu et al, 1989;Jeffery and Wanstall, 1999). IH combined with episodic hypercapnia accelerates atherosclerosis of PA in ApoE knockout mice and Ldlr knockout mice (Xue et al, 2017;Imamura et al, 2019), as illustrated by increases in the atherosclerotic area percentage of the PA lumen.…”

Fast cycling of intermittent hypoxia in a physiomimetic 3D environment: A novel tool for the study of the parenchymal effects of sleep apnea

“…It is also worth noting that although we focused only on the application of intermittent hypoxia, the setting could easily be used for also applying intermittent hypercapnia which parallels intermittent hypoxia in OSA and is another challenge to normal cell response. Alternatively, both intermittent hypoxia and hypercapnia could be also implemented easily by a pre-mixed gas source, thereby reproducibly simulating naturally occurring events in patients with OSA ( Imamura et al, 2019 ; Tripathi et al, 2019 ). However, we did not test intermittent hypercapnia because there is no available CO 2 sensor with the size and time resolutions required for this application.…”