Intermittent hypoxia and hypercapnia induces inhibitor of nuclear factor-kappaB kinase subunit beta-dependent atherosclerosis in pulmonary arteries.

摘要

Clinical studies have shown that obstructive sleep apnea (OSA) increases atherosclerosis risk. The inflammation, especially mediated by the macrophages via nuclear factor-KB (NF-kB), has been speculated to contribute to atherogenicity in OSA patients. Inhibitor of NF-kB kinase-beta (IKKbeta) is an essential element of the NF-kB 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 IKKbeta-dependent NF-kappaB activation in mono-cytes and macrophages plays a role in IHH-induced PA atherosclerosis. To test this hypothesis, myeloid restricted IKKbeta deletion (Ikkbeta~(DELTAMye)) or control (lkkbeta~(F/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 Ikkbeta~(DELTAMye);Ldlr~/~ and lkkbeta~(F/F);Ldlr~/~ male mice under IHH vs. Air. The results revealed that IKKp deletion abolished IHH-induced PA atherosclerosis after 8-wk exposure but not after 16-wk exposure (8 wk: lkkbeta~(F/F);Ldlr~/~, IHH 13.5 ± 1.4 vs. Air 5.7 ± 0.7%, P < 0.01; Ikkbeta~(DELTAMye);Ldlr~/~, IHH 7.4 ± 1.9% vs. Air 4.6 ± 1.3%, P = 0.24). Both IKKbeta deletion and IHH had no effects on atherosclerosis in the aorta. Our findings demonstrate that IKKbeta-dependent NF-kappaB activity in myeloid-lineage cells plays a critical role in IHH-induced PA atherosclerosis at the early stage.