Adenosine and the Cardiovascular System

Abstract

Adenosine is an endogenous nucleoside with a short half-life that regulates many physiological functions involving the heart and cardiovascular system. Among the cardioprotective properties of adenosine are its ability to improve cholesterol homeostasis, impact platelet aggregation and inhibit the inflammatory response. Through modulation of forward and reverse cholesterol transport pathways, adenosine can improve cholesterol balance and thereby protect macrophages from lipid overload and foam cell transformation. The function of adenosine is controlled through four G-protein coupled receptors: A₁, A_2A, A_2B and A₃. Of these four, it is the A_2A receptor that is in a large part responsible for the anti-inflammatory effects of adenosine as well as defense against excess cholesterol accumulation. A_2A receptor agonists are the focus of efforts by the pharmaceutical industry to develop new cardiovascular therapies, and pharmacological actions of the atheroprotective and anti-inflammatory drug methotrexate are mediated via release of adenosine and activation of the A_2A receptor. Also relevant are anti-platelet agents that decrease platelet activation and adhesion and reduce thrombotic occlusion of atherosclerotic arteries by antagonizing adenosine diphosphate-mediated effects on the P2Y12 receptor. The purpose of this review is to discuss the effects of adenosine on cell types found in the arterial wall that are involved in atherosclerosis, to describe use of adenosine and its receptor ligands to limit excess cholesterol accumulation and to explore clinically applied anti-platelet effects. Its impact on electrophysiology and use as a clinical treatment for myocardial preservation during infarct will also be covered. Results of cell culture studies, animal experiments and human clinical trials are presented. Finally, we highlight future directions of research in the application of adenosine as an approach to improving outcomes in persons with cardiovascular disease.

Figure 1. Intracellular and Extracellular Biogenesis of Adenosine

Adenosine is formed via dephosphorylation of ATP both inside and outside the cell. It can be formed intracellularly from ATP via adenylyl cyclase-mediated conversion of ATP to cAMP, which is then converted to AMP by phosphodiesterases. Subsequent activity of cytoplasmic 5’-nucleotidases convert AMP into adenosine, which can in turn be converted back to AMP through adenosine deaminase and adenosine kinase activity, with an inosine intermediate. A second intracellular pathway exists in which adenosine can be generated from S-adenosylhomocysteine (SAH) via SAH hydrolase. Extracellularly, ATP is converted to adenosine through the sequential action of ecto-nucleoside triphosphate diphosphohydrolase (ecto-NTPDase-1 [CD39]) that forms AMP, and ecto-5′nucleotidase (CD73) which converts AMP to adenosine

Figure 2. Electrophysiological Effects of Adenosine on the Heart

Adenosine acts at receptors in the atrium, sinus node, and atrioventricular (AV) node. A) The A1 adenosine receptor on cardiomyocytes mediates inotropic inhibitory actions of adenosine on contractility that are opposed by A2 adenosine receptor activation. Stimulation of specific cell-surface A1 receptors shortens the duration, depresses the amplitude, and reduces the rate of rise of the action potential of AV nodal cells, slowing impulse conduction through the AV node. Adenosine decreases spontaneous depolarization in the sinus node and conduction velocity in the AV node.

Figure 3. Methotrexate-Induced Adenosine Upregulation Attenuates Atherosclerotic Risk

Treatment with methotrexate (MTX) increases adenosine production which acts via the A2A receptor to upregulate various cholesterol efflux transporter proteins found on the macrophage cell membrane, namely: A) ATP-binding cassette subfamily A member 1 (ABCA1), which effluxes intracellular cholesterol in the form of apolipoprotein A-1, B) ATP binding cassette subfamily G member 1 (ABCG1), which effluxes intracellular cholesterol in the form of high-density lipoprotein (HDL), and C) 27-hydroxylase (27OH), which effluxes intracellular cholesterol in the form of 27-hydroxycholesterol. The formation and subsequent efflux of each of these cholesterol byproducts decrease the risk of lipid overload and foam cell formation of the macrophage, thereby decreasing the risk of atherosclerosis and eventual onset of cardiovascular disease.