The Role of Purinergic Signaling in Heart Transplantation

Abstract

Heart transplantation remains the optimal treatment option for patients with end-stage heart disease. Growing evidence demonstrates that purinergic signals mediated by purine nucleotides and nucleosides play vital roles in heart transplantation, especially in the era of ischemia-reperfusion injury (IRI) and allograft rejection. Purinergic signaling consists of extracellular nucleotides and nucleosides, ecto-enzymes, and cell surface receptors; it participates in the regulation of many physiological and pathological processes. During transplantation, excess adenosine triphosphate (ATP) levels are released from damaged cells, and driver detrimental inflammatory responses largely via purinergic P2 receptors. Ecto-nucleosidases sequentially dephosphorylate extracellular ATP to ADP, AMP, and finally adenosine. Adenosine exerts a cardioprotective effect by its anti-inflammatory, antiplatelet, and vasodilation properties. This review focused on the role of purinergic signaling in IRI and rejection after heart transplantation, as well as the clinical applications and prospects of purinergic signaling.

Keywords: ATP; adenosine; heart transplantation; ischemia reperfusion injury; purinergic signaling.

Figure 1

Schematic diagram of the strategy of the study. The main components of the purinergic signaling includes release of ATP, the hydrolysis of ATP to adenosine, the ecto-nucleotidases, transporters and purinergic receptors. The purinergic signaling exert immune regulation, vasodilation and antiplatelet functions, and play pivotal roles in heart preservation, IRI and rejection in heart transplantation (HTx).

Figure 2

Schematic diagram of purinergic signaling components, which consist of extracellular nucleotides and nucleosides, ecto-enzymes, and cell surface receptors. ATP is released from damaged cells or through the Pannexin-1 channel, and then is rapidly dephosphorylated to ADP and AMP by CD39, with AMP further catalyzed to adenosine by CD73. Purinergic receptors consist of P1 receptors and P2 receptors. P1 receptors bind with adenosine, which consist of A1, A2A, A2B and A3 receptors. A1Rs and A3Rs are coupled with Gi proteins and inhibit adenylate cyclase, whereas A2ARs and A2BRs coupled with Gs proteins and stimulate adenylate cyclase. P2 receptors consist of P2X and P2Y receptors, of which, P2XRs bind with ATP only, while P2YRs can bind with ATP, ADP, UTP, and UDP. Activation of P2XRs increases the concentration of intracellular Ca²⁺. Activation of P2YRs causes a change in the concentration of intracellular Ca²⁺ or cAMP.

Figure 3

Schematic diagram of the role of purinergic signaling in heart transplantation. ATP were released from damaged cells during the transplantation process. ATP were converted into ADP and AMP by CD39 and then catalyzed to adenosine by CD73. Extracellular ATP and ADP promote inflammatory responses and exacerbate detrimental rejection and cardiac ischemia reperfusion injury. Whereas, adenosine generally has anti-inflammatory and immunosuppressive properties, which protect the heart from rejection and ischemia reperfusion injury. Furthermore, the antiplatelet and vasodilatory effects of adenosine attenuate heart rejection and ischemia reperfusion injury.