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

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 (<i>Ldlr^-/-</i>) 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 (<i>Ikkβ^ΔMye</i>) or control (<i>Ikkβ^F/F</i>) mice were crossed with <i>Ldlr^-/-</i> 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 <i>Ikkβ^ΔMye</i>;<i>Ldlr^-/-</i> and <i>Ikkβ^F/F</i>;<i>Ldlr^-/-</i> 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: <i>Ikkβ^F/F</i>;<i>Ldlr^-/-</i>, IHH 13.5 ± 1.4 vs. Air 5.7 ± 0.7%, <i>P</i> < 0.01; <i>Ikkβ^ΔMye</i>;<i>Ldlr^-/-</i>, IHH 7.4 ± 1.9% vs. Air 4.6 ± 1.3%, <i>P</i> = 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.