Leukotriene B4 Receptor-1 Mediates Intermittent Hypoxia-induced Atherogenesis

Abstract

Rationale: Obstructive sleep apnea, which is characterized by intermittent hypoxia (IH) during sleep, has emerged as an independent risk factor for cardiovascular disease, including atherosclerosis. Leukotriene B4 (LTB4) production is increased in patients with obstructive sleep apnea and negatively correlates to hypoxic levels during sleep, with continuous positive airway pressure therapy decreasing LTB4 production. Objectives: Determine the potential role of LTB4 in IH-induced atherosclerosis in a monocyte cellular model and a murine model. Methods: THP-1 cells were exposed to IH for 3, 6, 24, and 48 hours. Macrophage transformation and foam cell formation were assessed after IH exposures. Apolipopotein E (ApoE)^−/− or BLT1^−/−/ApoE^−/− mice were fed an atherogenic diet and exposed to IH (alternating 21% and 5.7% O₂ from 7 am to 7 PM each day) for 10 weeks. Atherosclerotic lesion formation in en face aorta was examined by oil red O staining. Measurements and Main Results: IH increased production of LTB4 and the expression of 5-lipoxygenase and leukotriene A4 hydrolase, the key enzymes for producing LTB4. IH was associated with transformation of monocytes to activated macrophages, as evidenced by increased expression of CD14 and CD68. In addition, IH exposures promoted increased cellular cholesterol accumulation and foam cell formation. The LTB4 receptor 1 (BLT1) antagonist U-75302 markedly attenuated IH-induced changes. Furthermore, IH promoted atherosclerotic lesion formation in ApoE^−/− mice. IH-induced lesion formation was markedly attenuated in BLT1^−/−/ApoE^−/− mice. Conclusions: BLT1-dependent pathways underlie IH-induced atherogenesis, and may become a potential novel therapeutic target for obstructive sleep apnea–associated cardiovascular disease.