Cysteinyl-leukotriene pathway as a new therapeutic target for the treatment of atherosclerosis related to obstructive sleep apnea syndrome

Abstract

AimsObstructive 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 the role of CysLT in OSA-related atherosclerosis. Methods and resultsDeterminants of the urinary excretion of LTE4 (U-LTE4) including history of cardiovascular events, polysomnographic and biological parameters were studied in a cohort of 170 OSA patients and 29 controls, and in a subgroup of OSA patients free of cardiovascular event (n = 136). Mechanisms linking IH, the CysLT pathway and atherogenesis were investigated in Apolipoprotein E deficient (ApoE−/−) mice exposed to 8-week IH.In the whole cohort, U-LTE4 was independently influenced by age, minimal oxygen saturation, and a history of cardiovascular events, and correlated significantly with intima-media thickness. In the subgroup of OSA patients free of cardiovascular event, increased U-LTE4 was increased compared to controls and independently related to hypoxia severity and traditional risk factors aggregated in the 10-year cardiovascular risk score of European Society of Cardiology. In IH mice, atherosclerosis lesion size and mRNA levels of 5-lipoxygenase, 5-lipoxygenase activating protein (FLAP) and CysLT1 receptor were significantly increased. This transcriptional activation was associated with the binding of HIF-1 to the FLAP promoter and was strongly associated with atherosclerosis lesion size. CysLT1 receptor antagonism (montelukast) significantly reduced atherosclerosis progression in IH mice. ConclusionsIH-related CysLT pathway activation contributes to OSA-induced atherogenesis. In the era of personalized medicine, U-LTE4 may be a useful biomarker to identify OSA patients for whom CysLT1 blockade could represent a new therapeutic avenue for reducing cardiovascular risk.