title: Leukotriene B4 pathway activation and atherosclerosis in obstructive sleep apnea.
abstract: Leukotriene B(4) (LTB(4)) production increases in obstructive sleep apnea syndrome (OSA) and is linked to early vascular remodeling, the mechanism of which is unknown. The objective of this study was to to determine the molecular mechanisms of LTB(4) pathway activation in polymorphonuclear cells (PMNs) and early vascular remodeling in OSA and the specific contribution of intermittent hypoxia (IH). PMNs were isolated from 120 OSA patients and 33 healthy subjects and used for measurements of LTB(4) production, determination of mRNA and protein expression levels, or exposed for four cycles of in vitro IH. PMNs derived from OSA patients exhibited increased LTB(4) production, for which apnea-hypopnea index was an independent predictor (P=0.042). 5-Lipoxygenase-activating protein (FLAP) mRNA and protein increased significantly in PMNs from OSA patients versus controls and were associated with carotid luminal diameter and intima-media thickness. LTB(4) (10 ng/ml) increased IL-6 (P=0.006) and MCP-1 (P=0.002) production in OSA patient monocytes. In vitro exposure of PMNs from controls to IH enhanced FLAP mRNA levels (P= 0.027) and induced a 2.7-fold increase (P=0.028) in LTB(4) secretion compared with PMNs exposed to normoxia. In conclusion, upregulation of FLAP in PMNs in response to IH may participate in early vascular remodeling in OSA patients, suggesting FLAP as a potential therapeutic target for the cardiovascular morbidity associated with OSA.
authors: INSERM U1042, Grenoble, F-38042 France. FStanke@chu-grenoble.fr
authors: Françoise
authors: F
authors: Stanke-Labesque
authors: Jean-Louis
authors: JL
authors: Pépin
authors: Tiphaine
authors: T
authors: de Jouvencel
authors: Claire
authors: C
authors: Arnaud
authors: Jean-Philippe
authors: JP
authors: Baguet
authors: Marcelo H
authors: MH
authors: Petri
authors: Renaud
authors: R
authors: Tamisier
authors: Jean François
authors: JF
authors: Jourdil
authors: Patrick
authors: P
authors: Lévy
authors: Magnus
authors: M
authors: Bäck
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics; D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D015687:Cell Hypoxia; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000150:complications*
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D012333:RNA, Messenger; D007975:Leukotriene B4