Imamura Toshihiro, Poulsen Orit, Haddad Gabriel G
Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, California;
Department of Neurosciences, University of California, San Diego, California; and.
J Appl Physiol (1985). 2016 Sep 1;121(3):670-7. doi: 10.1152/japplphysiol.00307.2016. Epub 2016 Jul 28.
Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH). Clinical studies have previously shown that OSA is an independent risk factor for atherosclerosis. Atherogenicity in OSA patients has been assumed to be associated with the NF-κB pathways. Although foam cells are considered to be a hallmark of atherosclerosis, how IH as in OSA affects their development has not been fully understood. Therefore, we hypothesized that IH induces macrophage foam cell formation through NF-κB pathway activation. To test this hypothesis, peritoneal macrophages collected from myeloid-restricted IKK-β-deleted mice were incubated with native LDL and exposed to either IH or normoxia. After exposure, NF-κB pathway activity and intracellular cholesterol were measured. In control macrophages, IH significantly increased NF-κB pathway activity by 93% compared with normoxia (P < 0.05). However, such response to IH was diminished by IKK-β deletion (increased by +31% compared with normoxia; P = 0.64), suggesting that IKK-β is critical for IH-induced NF-κB pathway activation. Likewise, in control macrophages, total cholesterol was increased in IH compared with normoxia (65.7 ± 3.8 μg/mg cellular protein and 53.2 ± 1.2, respectively; P < 0.05). However, this IH-induced foam cell formation was disappeared when IKK-β was deleted (52.2 ± 1.2 μg/mg cellular protein for IH and 46.3 ± 1.7 for normoxia; P = 0.55). This IH-mediated effect still existed in macrophages without LDL receptor. Taken together, our findings show that IH activates the IKK-β-dependent NF-κB pathway and that this, in turn, induces foam cell formation in murine macrophages.
阻塞性睡眠呼吸暂停（OSA）是一种常见的睡眠障碍，其特征为间歇性缺氧（IH）。临床研究先前已表明，OSA是动脉粥样硬化的独立危险因素。OSA患者的动脉粥样硬化性被认为与核因子κB（NF-κB）信号通路有关。尽管泡沫细胞被视为动脉粥样硬化的标志，但OSA中的间歇性缺氧如何影响其形成尚未完全明确。因此，我们推测间歇性缺氧通过激活NF-κB信号通路诱导巨噬细胞泡沫细胞形成。为验证这一假设，将从骨髓限制性IKK-β基因敲除小鼠收集的腹腔巨噬细胞与天然低密度脂蛋白（LDL）一起孵育，并暴露于间歇性缺氧或常氧环境中。暴露后，检测NF-κB信号通路活性和细胞内胆固醇水平。在对照巨噬细胞中，与常氧相比，间歇性缺氧使NF-κB信号通路活性显著增加93%（P<0.05）。然而，IKK-β基因敲除减弱了对间歇性缺氧的这种反应（与常氧相比增加了31%；P = 0.64），表明IKK-β对间歇性缺氧诱导的NF-κB信号通路激活至关重要。同样，在对照巨噬细胞中，与常氧相比，间歇性缺氧时总胆固醇增加（分别为65.7±3.8μg/mg细胞蛋白和53.2±1.2μg/mg细胞蛋白；P<0.05）。然而，当IKK-β基因敲除时，这种间歇性缺氧诱导的泡沫细胞形成消失（间歇性缺氧时为52.2±1.2μg/mg细胞蛋白，常氧时为46.3±1.7μg/mg细胞蛋白；P = 0.55）。这种间歇性缺氧介导的效应在无LDL受体的巨噬细胞中仍然存在。综上所述，我们的研究结果表明，间歇性缺氧激活IKK-β依赖的NF-κB信号通路，进而诱导小鼠巨噬细胞中泡沫细胞形成。
