title: Intermittent hypoxia induces murine macrophage foam cell formation by IKK-β-dependent NF-κB pathway activation.
abstract: 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.
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, California; toshihiroimamrua@hotmail.com.
authors.forename: Toshihiro
authors.identifier: 0000-0002-9804-4583
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Neurosciences, University of California, San Diego, California; and.
authors.forename: Orit
authors.initials: O
authors.lastname: Poulsen
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, California; Department of Neurosciences, University of California, San Diego, California; and Rady Children's Hospital, San Diego, California.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
mesh_terms: D000818:Animals; D002460:Cell Line; D005487:Foam Cells / Q000276:immunology* / Q000473:pathology*; D000860:Hypoxia / Q000276:immunology*; D051550:I-kappa B Kinase / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse
keywords: IKK-β; NF-κB; foam cell; intermittent hypoxia; macrophage