Ticagrelor: a cardiometabolic drug targeting erythrocyte-mediated purinergic signaling?

Cardiometabolic diseases lead to vascular complications, which cause increasing morbidity and mortality worldwide. The underlying mechanisms are multifactorial and complex but may involve altered purinergic signaling that significantly contributes to cardiovascular dysfunction. Ticagrelor is a successful purinergic drug directly targeting ADP-mediated P2Y₁₂R signaling for platelet aggregation and is widely used in patients with acute coronary syndrome. In addition, ticagrelor can target red blood cells (RBCs) to release ATP and inhibit adenosine uptake by RBCs, which subsequently activate purinergic signaling. This involvement in purinergic signaling may allow ticagrelor to mediate pleiotropic effects and contribute to the beneficial cardiovascular outcomes observed in clinical studies. Recent studies have established a novel function of RBCs, which is that RBCs act as disease mediators for the development of cardiovascular complications in type 2 diabetes (T2D). RBC-released ATP is defective in T2D, which has implications for the induction of vascular dysfunction by dysregulating purinergic signaling. Ticagrelor might target RBCs and restore the bioavailability of ATP and adenosine, thereby attenuating cardiovascular complications. The present perspective discusses the pleiotropic effect of ticagrelor, with a focus on the possibility of ticagrelor for the treatment of cardiometabolic complications by targeting RBCs and initiating purinergic activation. A better understanding of the proposed cardiometabolic effects could support novel clinical indications for ticagrelor application.