Could the thromboxane A2 pathway be a therapeutic target for the treatment of obstructive sleep apnea-induced atherosclerosis?
Introduction
Obstructive sleep apnea (OSA) is a worldwide public health problem affecting 5–20% of the general population [1]. OSA is characterized by recurrent episodes of nocturnal upper airway collapses, leading to intermittent hypoxia (IH) that is detrimental for the cardiovascular system. Cardiovascular morbidity and mortality are in fact increased in patients suffering from OSA [2] and 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], [8], [9], all these experiments being performed in the absence of high-fat-diet.
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 IH-induced vascular remodeling [6], [7], [8], [9], [13], [14], [15], [16], [17], [18], [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], [21], [22]. Thromboxane A2 (TXA2) and prostacyclin (PGI2) are two COX-derived metabolites of arachidonic acid (AA). TXA2 is predominantly generated by platelets through the COX type 1 isoform (COX-1) and thromboxane synthase (TXBS), while PGI2 predominately results from the activity of the endothelial COX type 2 isoform (COX-2) and prostacyclin synthase (Fig. 1). As TXA2 and PGI2 are unstable, they are rapidly metabolized into various metabolites that are quantifiable in plasma and/or urine: 6-ketoprostagladin F1α (6-ketoPGF1α) and 2,3-dinor-6-ketoPGF1α for PGI2, thromboxane B2 (TXB2) and its derivatives 2,3-dinor-TXB2 and 11-dehydroTXB2 for TXA2 (Fig. 1). TXA2 and PGI2 exert their biologic effects through binding to distinct receptors, the TP and IP receptors, respectively, both expressed on platelets, vascular smooth muscle cells (VSMC), monocytes and endothelial cells. From a biological point of view, TXA2 and PGI2 have antagonist properties. TXA2 induces platelet activation, VSMC proliferation and vasoconstriction, and the expression of adhesion molecules, while PGI2 reduces platelet aggregation, chemotaxis and vasoconstriction (Fig. 1) (see review of Capra et al. [21]).
In addition to TXA2, others lipid mediators, i.e. the isoprostanoids, are able to bind to TP receptors [21], [23], mimicking the biological effects of TXA2 (Fig. 1). The isoprostanoids derived from AA via non-enzymatic oxidation include several isoprostanes: F-isoprostane, E-isoprostane and D-isoprostane.
Few studies have investigated the role of the TXA2-pathway in OSA-induced atherosclerosis; although this pathway has already been proposed as a therapeutic target for the treatment of cardiovascular diseases (see reviews [20], [21], [23]). The present review will focus on the role of the TXA2-pathway as a potential molecular link between OSA and atherosclerosis, and on the therapeutic interest of targeting TXA2 to reduce or prevent IH-induced atherogenesis.
Section snippets
Thromboxane A2 pathway activation in relation to intermittent hypoxia
The activation of the COX-pathway by IH has been demonstrated in clinical and animal studies, both at the systemic and tissue levels. We demonstrated that urinary 11-dehydroTXB2 concentrations in OSA patients free of cardiovascular comorbidities were not different from those of controls carefully matched for age and body mass index (BMI) [8]. Similarly, 11-dehydroTXB2 levels were similar in controls and mild-to-moderate OSA patients treated with antihypertensive drugs [24]. All these results
Therapeutic approaches to treat the OSA/IH-induced atherosclerosis
CPAP, the reference treatment of OSA, abolishes nocturnal apnea but fails to reduce cardiovascular risk in minimally symptomatic obese OSA patients [54], advocating for combined therapies [55] associating CPAP and pharmacological [56] or nutritional strategies targeting intermediary mechanisms leading to OSA related cardiovascular consequences.
Conclusion
As discussed in this review, there is a growing body of evidence from both experimental animal-model studies and clinical studies, suggesting that the TXA2-pathway could represent a molecular link between OSA and atherosclerosis. To summarize, IH and obesity the two major characteristic features of OSA seem to have a synergistic effect on the activation of the TXA2-pathway. TXA2 could therefore contribute to the development of atherosclerosis, particularly in obese OSA patients. Since CPAP
Acknowledgement
We thank Dr Alison Foote (Grenoble Clinical Research Centre) for language editing.
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