Adenosine and Its Receptors: An Expected Tool for the Diagnosis and Treatment of Coronary Artery and Ischemic Heart Diseases

Abstract

Adenosine is an endogenous nucleoside which strongly impacts the cardiovascular system. Adenosine is released mostly by endothelial cells and myocytes during ischemia or hypoxia and greatly regulates the cardiovascular system via four specific G-protein-coupled receptors named A1R, A2AR, A2BR, and A3R. Among them, A2 subtypes are strongly expressed in coronary tissues, and their activation increases coronary blood flow via the production of cAMP in smooth muscle cells. A2A receptor modulators are an opportunity for intense research by the pharmaceutical industry to develop new cardiovascular therapies. Most innovative therapies are mediated by the modulation of adenosine release and/or the activation of the A2A receptor subtypes. This review aims to focus on the specific exploration of the adenosine plasma level and its relationship with the A2A receptor, which seems a promising biomarker for a diagnostic and/or a therapeutic tool for the screening and management of coronary artery disease. Finally, a recent class of selective adenosine receptor ligands has emerged, and A2A receptor agonists/antagonists are useful tools to improve the management of patients suffering from coronary artery disease.

Hyperhomocysteinemia and Cardiovascular Disease: Is the Adenosinergic System the Missing Link?

“…The effectiveness of this transport system is particularly active in humans, and it is responsible for the extremely short half-life of adenosine in human blood. Adenosine, its receptors and nucleoside transporters together form the "adenosinergic system", which exerts fine regulation in multiple physiological and pathophysiological processes [135][136][137]. The transfer of adenosine to both sides of the cell is performed via specific proteins, called nucleoside transporters (NTs).…”

Endothelial Extracellular Vesicles: From Keepers of Health to Messengers of Disease

“…It has been well documented that biomarkers of endothelial dysfunction include vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1) and endothelial leukocyte adhesion molecule (ELAM-1) [ 159 ]. In addition, the presence of receptors, such as adenosine A2A receptor, on the membranes of circulating EVs in patients with coronary artery disease, may serve as biomarkers for endothelial dysfunction, although such EVs are likely released by cells other than endothelium [ 160 , 161 ]. However, what is truly needed to exploit EC-EVs for their diagnostic potential are tissue specific markers that will help in localizing the organ or tissue experiencing dysfunction.…”

Adenosine Receptor Reserve and Long-Term Potentiation: Unconventional Adaptive Mechanisms in Cardiovascular Diseases?

“…In this context, a mathematical model of the agonist–receptor interaction allowed the identification and quantification of spare adenosine receptors [ 10 ]. Peripheral blood mononuclear cells (PBMC) are used to evaluate the production and function of adenosine receptors in the cardiovascular system as the behavior of the adenosine receptors on PBMC mirror the behavior of these receptors in the heart [ 53 ], coronary arteries [ 54 ], and peripheral arteries [ 13 ]. Thus, the expression level and the cAMP production in PBMC are the same as in the cardiovascular tissues.…”

“…In CAD patients, the presence of spare receptors has been identified in patients with inducible ischemia, revealed by a low coronary flow fraction reserve [ 12 ] or by a positive stress test [ 30 ]. While one would expect an increase in A 2A R production to counteract the decrease in coronary blood flow, surprisingly, a decrease in A 2A R production in CAD patients with severe stenosis was observed [ 12 , 13 , 30 , 31 , 54 ]. We hypothesize that the first step of the adaptive mechanism in CAD to inducible ischemia is an asymptomatic and transient increase in A 2A R under chronic adenosine stimulation.…”

“…The receptor reserve depends upon three factors: (i) the agonist efficiency (i.e., concentration–effects relationship); (ii) the different functional states of the receptor and the tissue-dependent signal amplification [ 10 ]. In most cases, in the absence of spare receptors, the affinity constant value (K D ) is close to [ 11 ] or lower than the half-maximal value of the biological effects (EC 50 ) [ 12 , 13 ], depending on the nature of the receptor and ligand system.…”