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 A2B receptor (A2BAR) 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 A2BAR stimulation can decrease fibrosis through the inhibition of fibroblast proliferation and reduction in collagen synthesis. However, in contrast, there is also evidence that chronic A2BAR 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.

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

“…Likewise, bradykinin receptors, Gi-coupled BR1, and Gq-coupled BR2 have been shown to be expressed in cardiac myofibroblasts [99,100]. In addition, purinergic signaling has also been shown to play an important role in cardiac fibrosis [101,102]. For the P1 receptors (adenosine receptors), RT-PCR has shown that mRNAs for all four P1 receptor subtypes, A 1 AR, A 2A AR, A 2B AR, and A 3 AR, are expressed in rat cardiac fibroblasts, with A 2B ARs being the most abundant [102].…”

Therapeutic potential of A2 adenosine receptor pharmacological regulators in the treatment of cardiovascular diseases, recent progress, and prospective

“…Recently, adenosine and its analogs have emerged as potential therapeutic agents for treatment of numerous conditions from cancers to inflammatory diseases (Bahreyni, Samani, Khazaei, et al, ; Bahreyni et al, ). Consistently, there are several studies showing that both A2a and A2b ADORs are expressed in cardiovascular tissues and modulation of these receptors by adenosine or pharmacological molecules plays key roles in the regulation of heart rate, blood pressure, and heart rate variability in the cardiovascular system (Thomas et al, ; Vecchio, White, & May, ). As summarized in this review, although it is admitted that A2 ADOR subtypes have regulatory effects on the cardiovascular system and dysfunction of these receptors triggers CVD, the exact role of adenosine and its analogs in pathogenesis of CVD is quite controversial; therefore, further investigations are required to clarify the precise role of adenosine and A2 ADOR in the cardiovascular system.…”

Novel Targets in Reducing Cardiac Fibrosis as a Preventive Tool for Cardiovascular Diseases. Why Always Treat Them? A Review Article

“…In contrast, in the skin, liver, and lungs, adenosine A2A and A2B receptors both mediate an increase in fibrosis. It is also striking that different adenosine receptors appear to play a dominant role in fibrosis in different organs; adenosine A2A receptors are the dominant receptors in the skin, peritoneum, and liver but A2B receptors are responsible for pulmonary fibrosis (Bruce et al, 2011 andVecchio et al, 2017).…”