Ticagrelor Prevents Endothelial Cell Apoptosis through the Adenosine Signalling Pathway in the Early Stages of Hypoxia.

Catherine Feliu,Philippe Nguyen,Sylvie Brassart-Pasco,Hélène Peyret,Hervé Millart,Gaël Poitevin,Floriane Oszust,Zoubir Djerada

doi:10.3390/biom10050740

Abstract

Background: Several studies have reported the beneficial effects of anti-platelet drugs in cardioprotection against ischaemia–reperfusion injuries. To date, no studies have focused on the indirect cytoprotective effects of ticagrelor via adenosine receptor on the endothelium. Method: By evaluating cell viability and cleaved caspase 3 expression, we validated a model of endothelial cell apoptosis induced by hypoxia. In hypoxic endothelial cells treated with ticagrelor, we quantified the extracellular concentration of adenosine, and then we studied the involvement of adenosine pathways in the cytoprotective effect of ticagrelor. Results: Our results showed that 10 µM ticagrelor induced an anti-apoptotic effect in our model associated with an increase of extracellular adenosine concentration. Similar experiments were conducted with cangrelor but did not demonstrate an anti-apoptotic effect. We also found that A2B and A3 adenosine receptors were involved in the anti-apoptotic effect of ticagrelor in endothelial cells exposed to 2 h of hypoxia stress. Conclusion: we described an endothelial cytoprotective mechanism of ticagrelor against hypoxia stress, independent of blood elements. We highlighted a mechanism triggered mainly by the increased extracellular bioavailability of adenosine, which activates A2B and A3 receptors on the endothelium.

Highlights

Vascular endothelial lesions are associated with the death of apoptotic cells and dysfunction, leading to the development of atherosclerosis [1,2,3,4]
We validated the model with other markers as cell viability, as there was only apoptosis which was significantly expressed; we focused on an apoptotic model, a model which has not yet been studied at the endothelial level with ticagrelor as a trigger of cytoprotection
We studied the expression of adenosine receptors mRNA in human umbilical vein endothelial cells (HUVECs) at different times of hypoxia (T1h and T2h of hypoxia stress)

Summary

Introduction

Vascular endothelial lesions are associated with the death of apoptotic cells and dysfunction, leading to the development of atherosclerosis [1,2,3,4]. The same team reported that ticagrelor did not induce cardioprotection during ischaemia/reperfusion (I/R) injury in an ex-vivo cardiac model. Other studies have reported that the cardioprotective effects of ticagrelor, using in vivo ischaemia-reperfusion heart models, were associated with an increase in heart adenosine concentration [17]. We validated the model with other markers as cell viability, as there was only apoptosis which was significantly expressed; we focused on an apoptotic model, a model which has not yet been studied at the endothelial level with ticagrelor as a trigger of cytoprotection. We found that A2B and A3 adenosine receptors were involved in the anti-apoptotic effect of ticagrelor in endothelial cells exposed to 2 h of hypoxia stress. We highlighted a mechanism triggered mainly by the increased extracellular bioavailability of adenosine, which activates A2B and A3 receptors on the endothelium

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Methods

Results