Adenosine and the Cardiovascular System

Allison B. Reiss; David Grossfeld; Lora J. Kasselman; Heather A. Renna; Nicholas A. Vernice; Wendy Drewes; Justin Konig; Steven E. Carsons; Joshua DeLeon

Disclosures

Am J Cardiovasc Drugs. 2019;19(5):449-464. 

In This Article

Abstract and Introduction

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, A2A, A2B and A3. Of these four, it is the A2A receptor that is in a large part responsible for the anti-inflammatory effects of adenosine as well as defense against excess cholesterol accumulation. A2A 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 A2A 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.

Introduction

The endogenous, ubiquitous purine-nucleoside adenosine exerts multiple biochemical effects that serve important roles in cardiac and vascular biology.[1–3] Adenosine is known to regulate myocardial and coronary circulatory functions and exerts potent vasodilatory effects in most vascular beds of mammalian species.[4,5] Adenosine acts by at least four major types of G protein-coupled cell surface receptors, A1, A2A, A2B and A3,[6,7] which are encoded by distinct genes and are differentiated based on their affinities for adenosine agonists and antagonists.[8] All four receptors are N-linked glycoproteins. Adenosine receptors are ubiquitous and are activated by different ranges of endogenous adenosine concentrations.[8] A1 and A3 receptors are negatively coupled to adenylyl cyclase via interaction with pertussis toxin-sensitive G proteins of the Gi and Go family; A2 subtypes are cyclic adenosine-3′,5′-monophosphate (cAMP)-elevating, Gs protein-coupled receptors positively coupled to adenylyl cyclase.[9,10]

The widespread actions of adenosine include effects on multiple organs and systems including the heart,[11] nervous system,[12–14] lungs,[15] gastrointestinal system,[16] kidneys[17–19] and reproductive organs,[20,21] as well as on blood cells,[22] adipocytes,[23,24] and the immune system.[25,26] This review examines the role of adenosine in cardiovascular processes, both pathological and physiological. There is a focus on how they change lipid transport and platelet aggregation because these are two major factors in development and progression of atherosclerosis that are the targets for many current therapies.[27–30]

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