Background: Obstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl-leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and to precise the role of CysLT in OSA-related atherosclerosis. Methods: Determinants of the urinary excretion of LTE 4 (U-LTE 4 ) including history of cardiovascular events, polysomnographic and biological parameters were studied in 170 OSA patients and 29 controls. Mechanisms linking IH, CysLT pathway and IH-related atherogenesis were investigated in apolipoprotein E deficient (ApoE -/-) mice exposed to 8-week IH. Results: In humans, U-LTE 4 was independently influenced by age, minimal oxygen saturation and history of cardiovascular events. U-LTE 4 significantly correlated to left and mean carotid intima-media thickness. In IH mice, atherosclerosis lesion size and mRNA levels of 5-lipoxygenase, 5-lipoxygenase activating protein (FLAP), leukotriene A 4 hydrolase and CysLT 1 receptor were significantly increased. This transcriptional activation was associated with the binding of HIF-1 to the FLAP promoter and was strongly related to the atherosclerosis lesion size. Pharmacological blockade of CysLT 1 receptor by montelukast significantly reduced atherosclerosis progression in IH mice. Conclusions: IH-related CysLT pathway activation contributed to OSA-induced atherogenesis. In the era of personalized medicine, U-LTE 4 might be an interesting biomarker to identify OSA patients for whom CysLT 1 blockade might represent a new therapeutic avenue for reducing their cardiovascular risk.
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