Abstract 12988: Intermittent Hypoxia and Hypercapnia Induce Pulmonary Artery Atherosclerosis in Low Density Lipoprotein Receptor Deficient Mice by an NF-kappa B-dependent Mechanism

Abstract

Background: Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia and hypercapnia (IHH). Clinical studies have shown that OSA is an independent risk factor for atherosclerosis. In spite of its clinical importance and relevance, the contribution of IHH to atherogenicity has not yet been fully examined compared to the role of intermittent hypoxia exposure alone, which has been relatively well documented. We previously reported that IHH increased pulmonary artery (PA) but not aortic atherosclerosis in low-density lipoprotein receptor deficient (Ldlr-/-) mice. The mechanism of this IHH-induced PA atherosclerosis is unknown; however, previous studies have shown that various inflammatory mediators, particularly in the NF-kappa B (NF-kB) pathway, could cause atherosclerosis in OSA patients. Furthermore, it is known that the macrophages in atherosclerotic lesions play an important role as inflammatory cells involved in this process. Therefore, we hypothesized that IHH-induced PA atherosclerosis is caused by a macrophage NF-kB-dependent mechanism. Methods: Myeloid restricted IKK-beta deleted (Ikk-bΔMye) mice were generated by a Cre/lox recombination system to inactivate the NF-kB pathway in macrophages, and then crossed to Ldlr-/- mice to generate a double knockout animal (Ldlr-/-_Ikk-bΔMye). Male mice were fed with high-fat diet for 8 weeks while being exposed to IHH for 10 h/day. Plasma lipid levels, PA and aortic atherosclerotic lesions were then assayed. Results: The IKK-beta intact (Ldlr-/-_Ikk-bflox/flox) mice exposed to IHH developed more PA atherosclerotic lesions as compared to room air (RA) exposed mice (IHH 10.45%±5.07 vs. RA 5.68%±1.73). However, this IHH-induced PA atherogenicity was partially abolished in IKK-beta deleted mice (IHH 7.38%±4.71 and RA 4.58%±3.42). There was no significant difference in aortic atherogenicity among these four animal groups. Serum total cholesterol and triacylglycerol were increased after the implementation of high-fat diet but showed no difference among the groups during the course of this experiment. Conclusion: The macrophage NF-kB pathway plays a critical role in IHH-induced PA atherosclerosis and inactivation of NF-kB ameliorats such atheogenicity.