Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Salzburg, Austria.
Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H90-H94. doi: 10.1152/ajpheart.00570.2020. Epub 2020 Oct 23.
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 P2YR 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.
心血管代谢疾病导致血管并发症，在全球范围内导致发病率和死亡率不断上升。其潜在机制是多因素和复杂的，但可能涉及改变嘌呤能信号，这对心血管功能障碍有重大贡献。替格瑞洛是一种成功的嘌呤能药物，直接针对 ADP 介导的 P2YR 信号靶向血小板聚集，广泛用于急性冠脉综合征患者。此外，替格瑞洛可以靶向红细胞 (RBC) 释放 ATP 并抑制 RBC 摄取腺苷，随后激活嘌呤能信号。这种参与嘌呤能信号可能使替格瑞洛介导多效性作用，并有助于在临床研究中观察到的有益的心血管结果。最近的研究确立了 RBC 的一个新功能，即 RBC 作为 2 型糖尿病 (T2D) 心血管并发症发展的疾病介质。T2D 中 RBC 释放的 ATP 有缺陷，这对通过调节嘌呤能信号诱导血管功能障碍有影响。替格瑞洛可能靶向 RBC 并恢复 ATP 和腺苷的生物利用度，从而减轻心血管并发症。本观点讨论了替格瑞洛的多效性作用，重点探讨了替格瑞洛通过靶向 RBC 并启动嘌呤能激活治疗心血管代谢并发症的可能性。更好地理解拟议的心血管代谢作用可以为替格瑞洛的应用提供新的临床适应证。
