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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.
- Source :
-
Pharmacological research [Pharmacol Res] 2018 Aug; Vol. 134, pp. 311-319. Date of Electronic Publication: 2018 Jun 18. - Publication Year :
- 2018
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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.)
- Subjects :
- 5-Lipoxygenase-Activating Proteins genetics
5-Lipoxygenase-Activating Proteins metabolism
Acetates pharmacology
Adult
Animals
Arachidonate 5-Lipoxygenase genetics
Arachidonate 5-Lipoxygenase metabolism
Atherosclerosis metabolism
Atherosclerosis pathology
Atherosclerosis prevention & control
Case-Control Studies
Cyclopropanes
Cysteine antagonists & inhibitors
Cysteine urine
Disease Models, Animal
Disease Progression
Female
Humans
Leukotriene Antagonists pharmacology
Leukotriene E4 urine
Leukotrienes urine
Male
Mice, Knockout, ApoE
Middle Aged
Plaque, Atherosclerotic
Quinolines pharmacology
Receptors, Leukotriene drug effects
Receptors, Leukotriene genetics
Receptors, Leukotriene metabolism
Risk Factors
Signal Transduction drug effects
Sleep Apnea, Obstructive drug therapy
Sleep Apnea, Obstructive metabolism
Sulfides
Atherosclerosis etiology
Cysteine metabolism
Leukotrienes metabolism
Sleep Apnea, Obstructive complications
Subjects
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