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

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.

The Effect of Ticagrelor on Endothelial Function Compared to Prasugrel, Clopidogrel, and Placebo: A Systematic Review and Meta-Analysis

“…One hypothesis states that ticagrelor exerts vasoprotective effects by indirectly blocking adenosine phosphate receptors in addition to inhibition of platelet aggregation ( 46 ). Adenosine, a naturally occurring endogenous purine nucleotide, plays a crucial role in the endothelial cytoprotection of ticagrelor against hypoxia ( 6 ). Interestingly, it was suggested that ticagrelor might influence microvascular function through the platelet-endothelial pathway and the anti-inflammatory pathway ( 5 , 47 ).…”

Protective Role of Platelets in Myocardial Infarction and Ischemia/Reperfusion Injury

“…Additionally, ticagrelor was able to prevent endothelial cells against apoptosis due to hypoxia stress. e protective effect of ticagrelor was associated with the adenosine signaling pathway [151].…”

Myocardial Ischemia–Reperfusion Injury: Unraveling Pathophysiology, Clinical Manifestations, and Emerging Prevention Strategies

“…HEALING-AMI included patients with primary PCI-treated STEMI and were randomized to receive ticagrelor-versus clopidogrelbased DAPT and showed that ticagrelor was superior to clopidogrel with regard to left ventricle remodeling, as it was evaluated via a relative change of LVEDV volume measured on 3D echocardiogram and levels of N-terminal pro-B-type natriuretic peptide level [105]. Additionally, ticagrelor prevented endothelial cell apoptosis caused by hypoxia stress; this could be attributed to its effect on the adenosine signaling pathway [106].…”