Prostaglandins and Other Lipid Mediators ould the thromboxane A 2 pathway be a therapeutic target for the reatment of OSA-induced atherosclerosis ?

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal episodes of intermittent hypoxia. This disease is associated with premature atherosclerosis and consequently with increased cardiovascular morbidity and mortality. Atherosclerosis is a chronic inflammatory disease characterized by the activation of some components of the cyclooxygenase pathway. In particular, OSA is associated with activation of the thromboxane A2 (TXA2)-pathway, in which obesity seems to be a major confounding factor. Moreover, TXA2-pathway activation is related to the vascular remodeling associated with OSA. In view of the modest effect of the conventional treatment of OSA by continuous positive airway pressure on the cardiovascular risk in obese OSA patients, the identification of new therapeutic targets to treat OSAinduced atherosclerosis seems essential. As disruption of the TXA2-pathway has been suggested to be of potential interest to prevent atherosclerosis progression, we have reviewed the recent findings on the intricate interaction between the TXA2-pathway, chronic intermittent hypoxia and atherosclerosis and suggest promising therapeutic strategies to treat OSA-related atherogenesis, including pharmacological and/or nutritional approaches. © 2015 Published by Elsevier Inc. 27 28 29 30 31 32 ntroduction Obstructive sleep apnea (OSA) is a worldwide public health roblem affecting 5–20% of the general population [1]. OSA is haracterized by recurrent episodes of nocturnal upper airway ollapses, leading to intermittent hypoxia (IH) that is detrimental Please cite this article in press as: Gautier-Veyret E, et al. Could the th of OSA-induced atherosclerosis? Prostaglandins Other Lipid Mediat (2 or the cardiovascular system. Cardiovascular morbidity and morality are in fact increased in patients suffering from OSA [2] and Abbreviations: AA, arachidonic acid; AHI, apnea hypopnea index; ApoE−/− , polipoprotein E-deficient; BMI, body mass index; COX, cyclooxygenase; CPAP, coninuous positive airway pressure; DHA, docosahexanoic acid; EPA, eicosapentanoic cid; IH, intermittent hypoxia; IMT, intima-media thickness; OSA, obstructive sleep pnea; PGI2, prostacyclin (prostaglandin I2); PUFA, polyunsaturated fatty acid; 6etoPGF1 , 6-ketoprostaglandin F1 ; TXA2, thromboxane A2; TXB2, thromboxane 2; TXBS, thromboxane synthase; VSMC, vascular smooth muscle cells. ∗ Corresponding author at: CHU, Hôpital Albert Michallon, Laboratoire de harmacologie-Toxicologie, CS10217, F-38043 Grenoble Cedex 9, INSERM U1042, rance. Tel. : +33 4 76 76 54 92; fax: +33 4 76 76 89 38. E-mail address: FStanke@chu-grenoble.fr (F. Stanke-Labesque). ttp://dx.doi. org/10.1016/j.prostaglandins. 2015.05. 005 098-8823/© 2015 Published by Elsevier Inc. 33 34 35 36 37 38 39 40 41 42 43 OSA is now recognized as an independent cardiovascular risk factor [3]. Several studies have suggested that IH per se may promote early vascular remodeling. Indeed, OSA patients free of cardiovascular risk factors present early signs of atherosclerosis [4,5] that correlate to hypoxia severity [4,5] and are partially reversed by continuous positive airway pressure (CPAP) treatment [5]. Experimental animal studies have provided further evidence for the role of IH in the development of atherosclerosis. Chronic exposure to IH induced preatherosclerotic remodeling in lean mice [6] or an acceleration of atherogenesis in apolipoprotein E-deficient (ApoE−/−) mice [7–9], all these experiments being performed in the absence of high-fatdiet. Atherosclerosis [10] and OSA [11,12] are diseases associated with chronic low grade inflammation. Thus, several works have supported the hypothesis that the underlying inflammation induced by IH may be a determining factor that could contribute to romboxane A2 pathway be a therapeutic target for the treatment 015), http://dx.doi. org/10.1016/j.prostaglandins. 2015.05. 005 IH-induced vascular remodeling [6–9,13–19]. Among the numerous inflammatory mediators, the cyclooxygenase (COX)-pathway has been shown to play a major role in the onset and progression of atherosclerosis [20–22]. Thromboxane 44 45 46 47 ARTICLE IN PRESS G Model PRO 6123 1–8 2 E. Gautier-Veyret et al. / Prostaglandins & other Lipid Mediators xxx (2015) xxx–xxx Fig. 1. Biosynthesis and biological effects of thromboxane A2, prostacyclin and isoprostanes, and different therapeutic approaches to disrupt the thrombaxane A2 pathway. The enzymes synthesizing prostanoids are depicted in blue rectangles, whereas the white shaded rectangles indicate prostanoid receptors. The dotted arrows indicate the rapid degradation of thromboxane A2 and prostacyclin into various metabolites. Biological effects induced by receptor activation are indicated in large blue rectangles and the different therapeutic approaches are indicated in red rectangles. C SMC, A l p a a t r i 2 d T t o e h p m a