Targeting Adenosine Receptors for the Treatment of Cardiac Fibrosis

Abstract

Adenosine is a ubiquitous molecule with key regulatory and cytoprotective mechanisms at times of metabolic imbalance in the body. Among a plethora of physiological actions, adenosine has an important role in attenuating ischaemia-reperfusion injury and modulating the ensuing fibrosis and tissue remodeling following myocardial damage. Adenosine exerts these actions through interaction with four adenosine G protein-coupled receptors expressed in the heart. The adenosine A_2B receptor (A_2BAR) is the most abundant adenosine receptor (AR) in cardiac fibroblasts and is largely responsible for the influence of adenosine on cardiac fibrosis. In vitro and in vivo studies demonstrate that acute A_2BAR stimulation can decrease fibrosis through the inhibition of fibroblast proliferation and reduction in collagen synthesis. However, in contrast, there is also evidence that chronic A_2BAR antagonism reduces tissue fibrosis. This review explores the opposing pro- and anti-fibrotic activity attributed to the activation of cardiac ARs and investigates the therapeutic potential of targeting ARs for the treatment of cardiac fibrosis.

Keywords: adenosine; adenosine A2B receptor; cAMP; cardiac fibrosis; collagen synthesis; fibroblast; heart failure; myocardial infarction.

FIGURE 1

An overview of proposed adenosine receptor-mediated intracellular signaling pathways implicated in the regulation of cardiac fibrosis.