Could the thromboxane A2 pathway be a therapeutic target for the treatment of obstructive sleep apnea-induced atherosclerosis?

https://doi.org/10.1016/j.prostaglandins.2015.05.005Get rights and content

Highlights

  • Intermittent hypoxia and obesity may activate TXA2-pathway.

  • TXA2- pathway could be a link between OSA and atherosclerosis.

  • Pharmacological or nutritional approaches may disrupt TXA2-pathway.

  • These therapeutic strategies may treat atherosclerosis in obese OSA patients.

Abstract

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 OSA-induced 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.

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 F (6-ketoPGF) and 2,3-dinor-6-ketoPGF 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.

References (92)

  • M. Nácher et al.

    Biological consequences of oxygen desaturation and respiratory effort in an acute animal model of obstructive sleep apnea (OSA)

    Sleep Med

    (2009)
  • T. Ohmori et al.

    Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients

    J Thromb Haemost

    (2006)
  • F. Catella et al.

    Measurement of renal and non-renal eicosanoid synthesis

    Am J Med

    (1986)
  • L. Oztürk et al.

    Lipid peroxidation and osmotic fragility of red blood cells in sleep-apnea patients

    Clin Chim Acta

    (2003)
  • D. Monneret et al.

    Association of urinary 15-F2t-isoprostane level with oxygen desaturation and carotid intima-media thickness in nonobese sleep apnea patients

    Free Radic Biol Med

    (2010)
  • G.E. Carpagnano et al.

    8-Isoprostane, a marker of oxidative stress, is increased in exhaled breath condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy

    Chest

    (2003)
  • T. Cyrus et al.

    Thromboxane receptor blockade improves the antiatherogenic effect of thromboxane A2 suppression in LDLR KO mice

    Blood

    (2007)
  • C. Cherdon et al.

    BM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase

    Prostaglandins Other Lipid Mediat

    (2011)
  • T. Cyrus et al.

    A novel thromboxane receptor antagonist and synthase inhibitor, BM-573, reduces development and progression of atherosclerosis in LDL receptor deficient mice

    Eur J Pharmacol

    (2007)
  • D. Rott et al.

    Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice

    J Am Coll Cardiol

    (2003)
  • A.A. Weber et al.

    Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance

    Lancet

    (1999)
  • L. Belhassen et al.

    Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin

    J Am Coll Cardiol

    (2003)
  • P.C. Calder

    Mechanisms of action of (n-3) fatty acids

    J Nutr

    (2012)
  • K.H. Weylandt et al.

    Omega-3 fatty acids and their lipid mediators: towards an understanding of resolvin and protectin formation

    Prostaglandins Other Lipid Mediat

    (2012)
  • C. Pirich et al.

    Effects of fish oil supplementation on platelet survival and ex vivo platelet function in hypercholesterolemic patients

    Thromb Res

    (1999)
  • G. Kidson-Gerber et al.

    Serum thromboxane B2 compared to five other platelet function tests for the evaluation of aspirin effect in stable cardiovascular disease

    Heart Lung Circ

    (2010)
  • T. Young et al.

    The occurrence of sleep-disordered breathing among middle-aged adults

    N Engl J Med

    (1993)
  • H.K. Yaggi et al.

    Obstructive sleep apnea as a risk factor for stroke and death

    N Engl J Med

    (2005)
  • L.F. Drager et al.

    Early signs of atherosclerosis in obstructive sleep apnea

    Am J Respir Crit Care Med

    (2005)
  • C. Arnaud et al.

    The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition

    Am J Respir Crit Care Med

    (2011)
  • E. Gautier-Veyret et al.

    Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis

    Eur Respir J

    (2013)
  • G.K. Hansson

    Inflammation, atherosclerosis, and coronary artery disease

    N Engl J Med

    (2005)
  • S. Ryan et al.

    Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome

    Circulation

    (2005)
  • C. Arnaud et al.

    Obstructive sleep apnea, immuno-inflammation, and atherosclerosis

    Semin Immunopathol

    (2009)
  • Stanke-Labesque F, Bäck M, Lefebvre B, Tamisier R, Baguet J-P, Arnol N, et al. Increased urinary leukotriene E4...
  • S. Ryan et al.

    Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome?

    Postgrad Med J

    (2009)
  • B. Lefebvre et al.

    Leukotriene B4: early mediator of atherosclerosis in obstructive sleep apnoea?

    Eur Respir J

    (2008)
  • F. Stanke-Labesque et al.

    Leukotrienes as a molecular link between obstructive sleep apnoea and atherosclerosis

    Cardiovasc Res

    (2014)
  • V. Capra et al.

    Eicosanoids and their drugs in cardiovascular diseases: focus on atherosclerosis and stroke

    Med Res Rev

    (2013)
  • S.Y. Tang et al.

    Cyclooxygenase-2 in endothelial and vascular smooth muscle cells restrains atherogenesis in hyperlipidemic mice

    Circulation

    (2014)
  • D. Praticò et al.

    Vascular biology of eicosanoids and atherogenesis

    Expert Rev Cardiovasc Ther

    (2009)
  • A. Niżankowska-Jędrzejczyk et al.

    Modulation of inflammatory and hemostatic markers in obstructive sleep apnea patients treated with mandibular advancement splints: a parallel, controlled trial

    J Clin Sleep Med

    (2014)
  • H. Kimura et al.

    Compensatory excretion of prostacyclin and thromboxane metabolites in obstructive sleep apnea syndrome

    Intern Med

    (1998)
  • A.E. Beaudin et al.

    Cyclooxygenases 1 and 2 differentially regulate blood pressure and cerebrovascular responses to acute and chronic intermittent hypoxia: implications for sleep apnea

    J Am Heart Assoc

    (2014)
  • G. Davì et al.

    Platelet activation in obese women

    JAMA

    (2002)
  • A. Canales et al.

    Platelet aggregation, eicosanoid production and thrombogenic ratio in individuals at high cardiovascular risk consuming meat enriched in walnut paste. A crossover, placebo-controlled study

    Br J Nutr

    (2009)
  • Cited by (4)

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