Back to Search Start Over

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

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

Authors :
Gautier-Veyret E
Bäck M
Arnaud C
Belaïdi E
Tamisier R
Lévy P
Arnol N
Perrin M
Pépin JL
Stanke-Labesque F
Source :
Pharmacological research [Pharmacol Res] 2018 Aug; Vol. 134, pp. 311-319. Date of Electronic Publication: 2018 Jun 18.
Publication Year :
2018

Abstract

Aims: 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 the role of CysLT in OSA-related atherosclerosis.<br />Methods and Results: Determinants of the urinary excretion of LTE <subscript>4</subscript> (U-LTE <subscript>4</subscript> ) 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 <superscript>-/-</superscript> ) mice exposed to 8-week IH. In the whole cohort, U-LTE <subscript>4</subscript> 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-LTE <subscript>4</subscript> 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 CysLT <subscript>1</subscript> 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. CysLT <subscript>1</subscript> receptor antagonism (montelukast) significantly reduced atherosclerosis progression in IH mice.<br />Conclusions: IH-related CysLT pathway activation contributes to OSA-induced atherogenesis. In the era of personalized medicine, U-LTE <subscript>4</subscript> may be a useful biomarker to identify OSA patients for whom CysLT <subscript>1</subscript> blockade could represent a new therapeutic avenue for reducing cardiovascular risk.<br /> (Copyright © 2018. Published by Elsevier Ltd.)

Details

Language :
English
ISSN :
1096-1186
Volume :
134
Database :
MEDLINE
Journal :
Pharmacological research
Publication Type :
Academic Journal
Accession number :
29920371
Full Text :
https://doi.org/10.1016/j.phrs.2018.06.014